Re: Twin Sister with Acute Leukemia

[Guest guest]

Gubi,

There is very little that can be done for this woman for a variety of

reasons. AML is notoriously difficult. There are a couple of things that

she could explore. One is brusitol which is of natural origin and the other

is a type of dendritic cell vaccine that is in the works. There are other

things that may work on AML but I don't have a high enough degree of

confidence in them to pass them on.

(see below)

© Springer-Verlag 2002

Rapid generation of antigen-presenting cells from leukaemic blasts in acute

myeloid leukaemia

Theresia M. Westers1, Anita G. M. Stam2, Rik J. Scheper2, Johanna C.

Regelink1, Aggie W. M. Nieuwint3, Gerrit Jan Schuurhuis1, Arjan A. van de

Loosdrecht1 and Gert J. Ossenkoppele1,

(1) Department of Haematology, VU University Medical Centre, De Boelelaan

1117, Amsterdam, 1081 HV, the Netherlands

(2) Department of Pathology, VU University Medical Centre, Amsterdam, the

Netherlands

(3) Department of Clinical Genetics and Human Genetics, VU University

Medical Centre, Amsterdam, the Netherlands

Abstract. The ability of acute myeloid leukaemia (AML) cells to acquire

dendritic cell (DC)-like characteristics in vitro with a rapid culture

method based either on the phorbol ester PMA or calcium ionophores has been

studied in comparison to conventional AML-DC cultures with the cytokines

granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis

factor-alpha (TNF-), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML

patients, antigen-presenting cells (APC) could be generated from leukaemic

cells in 2 days by incubation with PMA or calcium ionophore (A23187 or

ionomycin) in the presence as well as in the absence of IL-4. In 30 out of

36 patients APC could be generated after 2 weeks of culture in

cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores

immunophenotypically and functionally were at a more mature stage than those

cultured in cytokine-enriched medium. The most mature APC were generated by

calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of

CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards

AML blast cells in vitro was observed in 2 cases tested. The persistence of

cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The

generation of AML-APC was possible from freshly isolated as well as

cryopreserved material. Our data show that generation of sufficient AML-APC

by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately

70% of AML specimens, offering a time-saving and cost-effective approach in

preparing anti-leukaemia vaccines.

Keywords. Acute myeloid leukaemia - A23187 - Calcium ionophore -

Cytotoxicity - Dendritic cell

Twin Sister with Acute Leukemia

> To whom it may concern within the cures for cancer group:

> Hi, I am writing from Lisbon, Portugal.

> I have joined this group today because I have a twin sister who has

> been diagnosed acute leukemia last December and, in order to be

> helpful any further to her, I need to find out more about this

> disease. She was at the time 7month pregnant (first baby) and upon a

> routine ecography she found out that her baby had died - she was sent

> immediatly to hospital where she was given blood transfusions, and

> medication that induced her, the following morning, to give birth to

> the dead baby without the possibility of an anesthesic...two hours

> later she underwent a mielogram (exam to the medula?) which confirmed

> the doctor's suspicion:acute leukemia, technical name " M 5 " . She

> stayed in hospital undergoing chemotherapy until last May, when she

> was informed that the disease seemed to be in remission. The medula

> transplant was not then considered a possibility as, unfortunately,

> none of us five brothers and sisters have compatible medulas (not

> even myself as her twin..) and using a medula from a donor outside

> the family was considered too risky in her case. She stayed out of

> the hospital until the 2nd of September, when, unexpectedly, the

> disease stroke back again. Ever since, she has underwent a High

> Density Chemotherapy which has not proved to be effective,

> unfortunately... As she has been feeling very depressed lately

> because her blood values are persistently low, last Wednesday she was

> exceptionally allowed to leave for a few days, having to stay home

> and taking lots of precautions to prevent any sort of infections -

> because next Monday she will start a second cycle of High density

> Chemotherapy - hoping that it will be effective this time!

> Her supervising doctor is considered an expert on the disease in

> Portugal, but on human terms she is someone difficult to approach -

> so, I wonder wether in this egroup there may be someone who might

> help me to find out more about the disease and, also, if there are

> any alternative sources of relief - compatible with the current chemo

> treatment prescribed - that may help her in this tough struggle.

> I apreciate the solidarity implied in this egroup and any possibly-

> helpful reply.

> All the best, Gubi

>

>

>

>

> Get HUGE info at http://www.cures for cancer.ws, and post your own links there.

Unsubscribe by sending email to cures for cancer-unsubscribeegroups or by

visiting http://www.bobhurt.com/subunsub.mv

>

>

[Guest guest]

Gubi,

There is very little that can be done for this woman for a variety of

reasons. AML is notoriously difficult. There are a couple of things that

she could explore. One is brusitol which is of natural origin and the other

is a type of dendritic cell vaccine that is in the works. There are other

things that may work on AML but I don't have a high enough degree of

confidence in them to pass them on.

(see below)

© Springer-Verlag 2002

Rapid generation of antigen-presenting cells from leukaemic blasts in acute

myeloid leukaemia

Theresia M. Westers1, Anita G. M. Stam2, Rik J. Scheper2, Johanna C.

Regelink1, Aggie W. M. Nieuwint3, Gerrit Jan Schuurhuis1, Arjan A. van de

Loosdrecht1 and Gert J. Ossenkoppele1,

(1) Department of Haematology, VU University Medical Centre, De Boelelaan

1117, Amsterdam, 1081 HV, the Netherlands

(2) Department of Pathology, VU University Medical Centre, Amsterdam, the

Netherlands

(3) Department of Clinical Genetics and Human Genetics, VU University

Medical Centre, Amsterdam, the Netherlands

Abstract. The ability of acute myeloid leukaemia (AML) cells to acquire

dendritic cell (DC)-like characteristics in vitro with a rapid culture

method based either on the phorbol ester PMA or calcium ionophores has been

studied in comparison to conventional AML-DC cultures with the cytokines

granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis

factor-alpha (TNF-), interleukin-3 (IL-3), SCF, FLT3-L and IL-4. In all AML

patients, antigen-presenting cells (APC) could be generated from leukaemic

cells in 2 days by incubation with PMA or calcium ionophore (A23187 or

ionomycin) in the presence as well as in the absence of IL-4. In 30 out of

36 patients APC could be generated after 2 weeks of culture in

cytokine-enriched medium. AML-APC cultured with PMA or calcium ionophores

immunophenotypically and functionally were at a more mature stage than those

cultured in cytokine-enriched medium. The most mature APC were generated by

calcium ionophore A23187 plus IL-4, as evidenced by the higher expression of

CD40, CD80, CD86 and HLA-DR. Autologous T cell mediated cytotoxicity towards

AML blast cells in vitro was observed in 2 cases tested. The persistence of

cytogenetic abnormalities confirmed the leukaemic origin of the AML-APC. The

generation of AML-APC was possible from freshly isolated as well as

cryopreserved material. Our data show that generation of sufficient AML-APC

by A23187 plus IL-4 is feasible, for vaccination purposes, in approximately

70% of AML specimens, offering a time-saving and cost-effective approach in

preparing anti-leukaemia vaccines.

Keywords. Acute myeloid leukaemia - A23187 - Calcium ionophore -

Cytotoxicity - Dendritic cell

Twin Sister with Acute Leukemia

> To whom it may concern within the cures for cancer group:

> Hi, I am writing from Lisbon, Portugal.

> I have joined this group today because I have a twin sister who has

> been diagnosed acute leukemia last December and, in order to be

> helpful any further to her, I need to find out more about this

> disease. She was at the time 7month pregnant (first baby) and upon a

> routine ecography she found out that her baby had died - she was sent

> immediatly to hospital where she was given blood transfusions, and

> medication that induced her, the following morning, to give birth to

> the dead baby without the possibility of an anesthesic...two hours

> later she underwent a mielogram (exam to the medula?) which confirmed

> the doctor's suspicion:acute leukemia, technical name " M 5 " . She

> stayed in hospital undergoing chemotherapy until last May, when she

> was informed that the disease seemed to be in remission. The medula

> transplant was not then considered a possibility as, unfortunately,

> none of us five brothers and sisters have compatible medulas (not

> even myself as her twin..) and using a medula from a donor outside

> the family was considered too risky in her case. She stayed out of

> the hospital until the 2nd of September, when, unexpectedly, the

> disease stroke back again. Ever since, she has underwent a High

> Density Chemotherapy which has not proved to be effective,

> unfortunately... As she has been feeling very depressed lately

> because her blood values are persistently low, last Wednesday she was

> exceptionally allowed to leave for a few days, having to stay home

> and taking lots of precautions to prevent any sort of infections -

> because next Monday she will start a second cycle of High density

> Chemotherapy - hoping that it will be effective this time!

> Her supervising doctor is considered an expert on the disease in

> Portugal, but on human terms she is someone difficult to approach -

> so, I wonder wether in this egroup there may be someone who might

> help me to find out more about the disease and, also, if there are

> any alternative sources of relief - compatible with the current chemo

> treatment prescribed - that may help her in this tough struggle.

> I apreciate the solidarity implied in this egroup and any possibly-

> helpful reply.

> All the best, Gubi

>

>

>

>

> Get HUGE info at http://www.cures for cancer.ws, and post your own links there.

Unsubscribe by sending email to cures for cancer-unsubscribeegroups or by

visiting http://www.bobhurt.com/subunsub.mv

>

>

[Guest guest]

From: " gubi6363 " <gubi6363@...>

<cures for cancer >

Sent: Friday, October 10, 2003 11:05 AM

Subject: Twin Sister with Acute Leukemia

Hi,

this isn't medical advice, just some things to follow up on.........

1: Br J Haematol 2002 Mar;116(3):555-63

Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia

myeloid cell lines: induction of apoptosis and inhibition of proliferation.

Rojewski MT, Baldus C, Knauf W, Thiel E, Schrezenmeier H.

Freie Universitat Berlin, Universitatsklinikum lin, Medizinische

Klinik III (Hamatologie, Onkologie und Transfusionsmedizin), Berlin, Germany.

Clinical efficacy of As2O3 has been shown in patients with relapsed acute

promyelocytic leukaemia (APL). There is evidence that the effects of As2O3 are

not restricted to events specific for APL. As2O3 might target mechanisms

involved in the pathogenesis of other malignancies. We assessed susceptibility

to induction of apoptosis by As2O3 and cytostatics in 22 myeloid and non-myeloid

malignant cell lines. As2O3 was used in concentrations of 0center dot01--10

micromol/l. Cell lines displayed different kinetics of response and different

sensitivity to As2O3. The minimum concentration of As2O3 for induction of

apoptosis was 0center dot1 micromol/l. High concentrations of As2O3 (5

micromol/l) induced apoptosis in a large proportion of cells in all cell lines

tested. Low (1 micromol/l As2O3) concentrations induced apoptosis in NB-4,

HL-60, U-937, CEM, HL-60, KG-1a, PBL-985, ML-2 and MV-4--11, but not in HEL,

K-562, KG-1 and Jurkat up to 35 d of incubation. However, the non-apoptotic

population of 1 micromol/l As2O3-treated HEL, K-562, K-562 (0center dot02),

K-562(0center dot1) and Jurkat showed reduced proliferation. CEM as well as its'

multidrug-resistant derivatives were sensitive to 1 micromol/l As2O3. In

summary, these data demonstrate that As2O3-induced apoptosis is not restricted

to cell lines with t(15;17). Apoptosis was induced in vitro by As2O3

concentrations that are achievable in vivo after infusion of well-tolerated

As2O3 doses. Thus, As2O3 might be a suitable therapeutic agent for malignancies

other than APL provided the adequate dose and duration of As2O3 treatment are

used.

PMID: 11849211 [PubMed - in process]

2: Chin Med J (Engl) 2000 Jun;113(6):498-501

[Potentiation of arsenic trioxide-induced apoptosis by retinoic acid in retinoic

acid sensitive and resistant HL-60 myeloid leukemia cells]

[Article in Chinese]

Huang X.

Institute of Hematology, People's Hospital, Beijing Medical University, Beijing

100044, China.

OBJECTIVE: To study the effect of arsenic trioxide (As2O3) on non-APL acute

myeloid leukemia (AML) cells and the interreactive effect between retinoic acid

(RA) and As2O3. METHODS: RA-sensitive (S) and RA-resistant ® HL-60 non-APL AML

cells were used as an in vitro model. Cell number and trypan blue were used to

observe cell growth and survival. Apoptosis was determined by morphological

changes, using a DNA laddering assay, terminal deoxynucleotidyl transferase

(TdT) fragment end labeling assay and a flow cytometry assay. RESULTS: As2O3

induced apoptosis in both HL-60S and HL-60R cells, As2O3-induced apoptosis was

both time- and concentration-dependent in a therapeutically-achievable As2O3

range (0.25-4.0 mumol/L). Both all-trans retinoic acid (ATRA) and 9-cis retinoic

acid (9cRA) potentiated As2O3-induced apoptosis, as measured by quantitative TdT

fragment and labeling and flow cytometry assays in both HL-60S and HL-60R cells

(P < 0.05, for all RA + As2O3 combinations vs As2O3 alone in both sublines).

CONCLUSIONS: As2O3 may inhibit the growth of non-APL AML cells by promoting

programmed cell death. RA can potentiate As2O3-induced apoptosis even in

RA-resistant HL-60 cells in which the classical ATRA response pathway is

repressed owing to a homozygous inactivating mutation in the retinoic acid

receptor alpha. As2O3 can have clinical activity in non-APL cases of AML and the

enhanced activity might result from the combined As2O3-RA therapy.

PMID: 11775865 [PubMed - indexed for MEDLINE]

3: Br J Haematol 2001 Mar;112(3):783-6

Arsenic trioxide and ascorbic acid: synergy with potential implications for the

treatment of acute myeloid leukaemia?

Bachleitner-Hofmann T, Gisslinger B, Grumbeck E, Gisslinger H.

Department of Internal Medicine I, Division of Haematology and Blood

Coagulation, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna,

Austria.

Arsenic trioxide (As2O3) induces remission in a high proportion of patients with

acute promyelocytic leukaemia (APL) via induction of apoptosis. Preliminary

reports suggest that the apoptotic effect of As2O3 is not specific for APL but

can also be observed in non-APL acute myeloid leukaemia (AML) cells, although

these are less sensitive than APL cells. Ascorbic acid has recently been

demonstrated to enhance the apoptotic effect of As2O3. We have therefore

evaluated combined As2O3/ascorbic acid treatment in various clinical samples of

AML. Our results indicate a significant synergistic effect of As2O3 and ascorbic

acid, suggesting a possible future role of As2O3/ascorbic acid combination

therapy in patients with AML.

Publication Types:

Evaluation Studies

PMID: 11260084 [PubMed - indexed for MEDLINE]

4: Blood 2000 Feb 1;95(3):1014-22

Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells

that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L).

Perkins C, Kim CN, Fang G, Bhalla KN.

Division of Clinical and Translational Research, Sylvester Comprehensive Cancer

Center, University of Miami School of Medicine, Miami, FL 33136, USA.

We investigated the in vitro growth inhibitory and apoptotic effects of

clinically achievable concentrations of As(2)O(3) (0.5 to 2.0 micromol/L)

against human myeloid leukemia cells known to be resistant to a number of

apoptotic stimuli. These included chronic myelocytic leukemia (CML) blast crisis

K562 and HL-60/Bcr-Abl cells, which contain p210 and p185 Bcr-Abl, respectively,

and HL-60 cell types that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-x(L)

(HL-60/Bcl-x(L)), MDR (HL-60/VCR), or MRP (HL-60/AR) protein. The

growth-inhibitory IC(50) values for As(2)O(3) treatment for 7 days against all

these cell types ranged from 0.8 to 1.5 micromol/L. Exposure to 2 micromol/L

As(2)O(3) for 7 days induced apoptosis of all cell types, including

HL-60/Bcr-Abl and K562 cells. This was associated with the cytosolic

accumulation of cyt c and preapoptotic mitochondrial events, such as the loss of

inner membrane potential (DeltaPsim) and the increase in reactive oxygen species

(ROS). Treatment with As(2)O(3) (2 micromol/L) generated the activities of

caspases, which produced the cleavage of the BH3 domain containing proapoptotic

Bid protein and poly (ADP-ribose) polymerase. Significantly, As(2)O(3)-induced

apoptosis of HL-60/Bcr-Abl and K562 cells was associated with a decline in

Bcr-Abl protein levels, without any significant alterations in the levels of

Bcl-x(L), Bax, Apaf-1, Fas, and FasL. Although As(2)O(3 )treatment caused a

marked increase in the expression of the myeloid differentiation marker CD11b,

it did not affect Hb levels in HL-60/Bcr-Abl, K562, or HL-60/neo cells. However,

in these cells, As(2)O(3 )potently induced hyper-acetylation of the histones H3

and H4. These findings characterize As(2)O(3) as a growth inhibiting and

apoptosis-inducing agent against a variety of myeloid leukemia cells resistant

to multiple apoptotic stimuli.

PMID: 10648417 [PubMed - indexed for MEDLINE]

5: Med Oncol 1999 Apr;16(1):58-64

Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of

caspases.

Huang XJ, Wiernik PH, Klein RS, Gallagher RE.

Department of Oncology, Montefiore Medical Center, The Albert Einstein Cancer

Center, Bronx, NY 10467, USA.

The primary objective of this study was to determine whether caspases are

involved in arsenic trioxide(ATO)-induced apoptosis of human myeloid leukemia

cells. A secondary objective was to determine whether apoptosis induced by ATO

compared with VP-16 is differentially affected by an activator of protein kinase

C (PKC), phorbol 12-myristate 13-acetate (PMA), which has been reported to

inhibit apoptosis induced by some chemotherapeutic agents. NB4 and HL60 cells

were incubated with ATO in the presence and absence of the caspase protease

inhibitors Z-VAD.fmk or Y-VAD.cho. Apoptosis was assessed by morphology, DNA

laddering and flow cytometry. Poly (ADP-ribose) polymerase (PARP) cleavage was

used as a marker for the activation of caspases. PARP cleavage occurred during

ATO-induced apoptosis in both NB4 and HL60 cells. Z-VAD.fmk, a broad-spectrum

inhibitor, could block ATO-induced apoptosis and PARP cleavage, whilst

Y-VAD.cho, a selective inhibitor of caspase 1, had no such effect. PMA

pre-incubation for up to 8 hours under conditions known to activate PKC had no

effect on either ATO- or VP-16-induced apoptosis. We conclude that in cultured

myeloid leukemia cells ATO-induced apoptosis is executed by caspases from the

distal, PARP-cleaving part of the activation cascade and that PKC activation has

no effect on apoptosis induced by either ATO or VP-16 in these cells.

PMID: 10382944 [PubMed - indexed for MEDLINE]

6: Cancer Res 1999 Feb 15;59(4):776-80

Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells.

Li YM, Broome JD.

Department of Laboratories, North Shore University Hospital, Manhasset, New York

11030, USA. YMLI@...

Arsenic exhibits a differential toxicity to cancer cells. At a high

concentration (>5 microM), As2O3 causes acute necrosis in various cell lines. At

a lower concentration (0.5-5 microm), it induces myeloid cell maturation and an

arrest in metaphase, leading to apoptosis. As2O3-treated cells have features

found with both tubulin-assembling enhancers (Taxol) and inhibitors

(colchicine). Prior treatment of monomeric tubulin with As2O3 markedly inhibits

GTP-induced polymerization and microtubule formation in vitro but does not

destabilize GTP-induced tubulin polymers. Cross-inhibition experiments indicate

that As2O3 is a noncompetitive inhibitor of GTP binding to tubulin. These

observations correlate with the three-dimensional structure of beta-tubulin and

suggest that the cross-linking of two vicinal cysteine residues (Cys-12 and

Cys-213) by trivalent arsenic inactivates the GTP binding site. Furthermore,

exogenous GTP can prevent As2O3-induced mitotic arrest.

PMID: 10029061 [PubMed - indexed for MEDLINE]

7: Blood 1998 Sep 1;92(5):1497-504

Arsenic trioxide and melarsoprol induce programmed cell death in myeloid

leukemia cell lines and function in a PML and PML-RARalpha independent manner.

Wang ZG, Rivi R, Delva L, Konig A, Scheinberg DA, Gambacorti-Passerini C,

Gabrilove JL, Warrell RP Jr, Pandolfi PP.

Department of Human Genetics, Molecular Biology Program, and the Molecular

Therapeutics Program, the Sloan-Kettering Institute, Graduate School of Medical

Sciences, Cornell University, New York, NY, 10021, USA.

Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were

recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic

leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has

been proposed to principally target PML and PML-RARalpha proteins in APL cells.

We investigated the activity of As2O3 and melarsoprol in a broader context

encompassing various myeloid leukemia cell lines, including the APL cell line

NB4-306 (a retinoic acid-resistant cell line derived from NB4 that no longer

expresses the intact PML-RARalpha fusion protein), HL60, KG-1, and the

myelomonocytic cell line U937. To examine the role of PML in mediating arsenical

activity, we also tested these agents using murine embryonic fibroblasts (MEFs)

and bone marrow (BM) progenitors in which the PML gene had been inactivated by

homologous recombination. Unexpectedly, we found that both compounds inhibited

cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell

lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations

ranging from 10(-7) to 10(-5) mol/L. As2O3 relocalized PML and PML-RARalpha onto

nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60

and U937 cell lines. Although melarsoprol was more potent in inhibiting growth

and inducing apoptosis, it did not affect PML and/or PML-RARalpha nuclear

localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth

and induced apoptosis of PML+/+ and PML-/- MEFs, and inhibited colony-forming

unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of

PML+/+ and PML-/- progenitors. Together, these results show that As2O3 and

melarsoprol inhibit growth and induce apoptosis independent of both PML and

PML-RARalpha expression in a variety of myeloid leukemia cell lines, and suggest

that these agents may be more broadly used for treatment of leukemias other than

APL. Copyright 1998 by The American Society of Hematology.

PMID: 9716575 [PubMed - indexed for MEDLINE]

Curcumin as an inhibitor of cancer.

J Am Coll Nutr, 64(2):192-8 1992 Apr

Curcumin I (Cur I) and curcumin III (Cur III) are the

yellow coloring phenolic compounds isolated from the spice

turmeric. The effect of curcumins on different stages of

development of cancer was studied. Cur I inhibited

benzopyrene- (BP) induced forestomach tumors in female

Swiss mice, and Cur III inhibited dimethylbenzanthracene-

(DMBA) induced skin tumors in Swiss bald mice. Cur I also

inhibited DMBA-initiated, tetradeconyl phorbol

acetate-promoted skin tumors in female Swiss mice. In

vitro 3H-BP-DNA interaction studies, and in vivo

carcinogen metabolizing enzyme studies revealed that

curcumins exert anticarcinogenic activity by altering the

activation and/or detoxification process of carcinogen

metabolism. Cur I and Cur III also exhibit in vitro

cytotoxicity against human chronic myeloid leukemia, which

is dose dependent. This study shows that curcumins inhibit

cancer at initiation, promotion and progression stages of

development.

Sponsor: Blood Online is sponsor

* Li, Y. M., Broome, J. D. (1999). Arsenic Targets Tubulins to Induce

Apoptosis in Myeloid Leukemia Cells. Cancer Res 59: 776-780

[Abstract] [Full Text]

C., Gabrilove, J. L., Warrell, R. P. Jr, Pandolfi, P. P. (1998).

Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in

Myeloid Leukemia Cell Lines and Function in a PML and PML-RARalpha

Independent Manner. Blood 92: 1497-1504 [Abstract] [Full Text]

1: Cancer Chemother Pharmacol 1999;44(5):417-21

Clinical study of an organic arsenical, melarsoprol, in patients with advanced

leukemia.

Soignet SL, Tong WP, Hirschfeld S, Warrell RP Jr.

Developmental Chemotherapy, Department of Medicine, Memorial Sloan-Kettering

Cancer Center, Cornell University Medical College, 1275 York Avenue, New York,

NY 10021, USA. soignets@...

Inorganic arsenic trioxide (As(2)O(3)) induces a high proportion of complete

remissions in relapsed patients with acute promyelocytic leukemia (APL).

Previously, we have shown that both As(2)O(3 )and melarsoprol, an organic

arsenical used for the treatment of trypanosomiasis, exhibit broad antileukemic

activity against both chronic and acute myeloid and lymphoid leukemia cell

lines. Given the breadth of this activity, we initiated a clinical study to

evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in

patients with refractory or resistant leukemia. Using the antitrypanosomal dose

and schedule, patients received escalating intravenous doses daily for 3 days,

repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and

3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200

mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean

peak plasma concentrations of the parent drug were obtained immediately after

injection, ranged from 1.2 microg/ml on day 1 to 2.4 microg/ml on day 3, were

dose proportional, and decayed with a t(1/2) congruent with 15 min. A minor

clinical response (regression of splenomegaly and lymphadenopathy) was observed

in a patient with chronic lymphocytic leukemia. Central nervous system (CNS)

toxicity proved limiting on this dose and schedule. Three patients experienced

generalized grand mal seizures during the second week of therapy. We concluded

that this dose and schedule of melarsoprol is associated with excessive CNS

toxicity and that verification of the striking preclinical activity in patients

with leukemia will require developing an alternative dose and schedule.

Publication Types:

Clinical Trial

Clinical Trial, Phase I

Multicenter Study

PMID: 10501916 [PubMed - indexed for MEDLINE]

1: Blood Rev 1997 Mar;11(1):39-45

High-dose cytosine arabinoside in the treatment of acute myeloid leukaemia.

Cole N, Gibson BE.

Department of Haematology, Royal Hospital for Sick Children, Glasgow, UK.

Cytosine arabinoside (Ara-C) has earned its recognition as the most important

antileukaemic drug currently available for the treatment of acute myeloid

leukaemia. Approximately 60-80% of patients less than 60 years of age can be

expected to enter complete remission if treated with standard-dose Ara-C

(100-200 mg/m2) in combination with an anthracycline. The efficacy of Ara-C

appears clinically to be dose and schedule dependent. A 15-30 fold dose

escalation in Ara-C can elicit a therapeutic response in patients who have

previously failed treatment with standard-dose Ara-C or other anti-leukaemic

drugs. The use of high-dose cytosine arabinoside (HDAC 3 gm/m2) appears rational

based on cytosine pharmacology. Drug-scheduling is used to exploit drug synergy

when HDAC is given in combination with asparaginase or fludarabine (+/- G-CSF)

in a schedule-dependent fashion. Toxicity following Ara-C is also dose- and

schedule-dependent. Central nervous system toxicity--particularly cerebellar

dysfunction--although rare, is particularly serious because it may preclude

further use of the drug. Older patients are particularly susceptible. This

article will describe the rationale for and the value of HDAC alone or in

combination with other cytotoxics in the treatment of acute myeloid leukaemia.

[Hindustan Times]

Last updated 22:00 IST | Monday, May 28, 2001, New Delhi

Has the ultimate cancer cure arrived?

(Hyderabaad, May 28)

INDIAN CANCER researchers have taken a giant step on the road

to discovering the ultimate cancer cure by developing a drug

that selectively targets the cancer cells without harming the healthy ones.

Researchers in Kolkata claim that patients in " very advanced

stages " of cancer for whom all other treatments had failed

have been brought back to " excellent " health with the help of Others....

a drug formulation they have developed after research

spanning more than a decade.

" We have what we think magic bullet against cancer, " says

Cultivation of Science (IACS) where the drug was developed

under a project funded by the Department of Science and

Technology and the Council of Scientific and Industrial

bail

Most currently available anti-cancer drugs are toxic because

they also damage the normal cells. Ray says the IACS

formulation, containing " Methylglyoxal " as the lead

ingredient, combats only the diseased cells, the cherished

goal of cancer researchers worldwide. Methylglyoxal is a

metabolite in the human body produced during glucose

breakdown.

Others involved in the project are Swapna Ghosh of IACS,

Manoj Kar and Subhankar Ray of the University College of

Science, and Santajit Datta, a medical practitioner. Results

of human trial conducted by them with the new drug have

recently appeared in the Indian Journal of Physics.

While Americans are going ga-ga with their new anti-cancer

drug " Glivec " - that was featured on the cover of May 28

issue of Time magazine - the low-profile, cash-strapped

Kolkata researchers have been working quietly for over a

decade shunning publicity until they obtained proof from

human trials nine weeks ago.

According to their published paper, the Methylglyoxal-based

forumulation had " a dramatic positive effect on the

patients " .

For instance, the condition of 11 out of the 19 patients

treated - most of them in a very advanced stage when the

treatment began -- are now stated to be in " excellent

physical condition " . Five are in stable condition and only

three died during the course of the study.

Since the submission of the paper, the number of patients

treated has crossed 40 mark with more than 70 per cent

success, according to Manju Ray.

Most remarkable fact, according to the scientists was that

Methylglyoxal was successful against different types of

cancer unlike " Glivec " which targets only the chronic myeloid

leukemia.

Those whose health returned to " excellent " condition after

treatment with Methylglyoxal included patients in " a very

advanced stages " of colon cancer, acute myeloid leukemia,

non-Hodgkin's lymphoma, and cancers of ovary, breast, liver,

lung, bone, gall bladder, pancreas and oral cavity.

The patients were inducted for the trial, from January to

June 2000, after obtaining permission from the Drug

Controller General of India, the scientists said. The drug

was administered orally for about six months with gradual

reduction of daily dosage from the initial 25 milligrams per

kilogram of body weight.

refuses formal

Researchers said development of the drug was preceded by

years of basic research involving human cancer cells in

culture and animal experiments that showed that Methylglyoxal

* selectively killed the cancer cells without affecting normal

cells by exploiting " a very significant " biochemical

difference between the two.

Explaining the mechanism of action, the scientists said

cancer cells required a large amount of energy providing

substance called ATP (Adenosine-5-Triphosphate) for survival.

" Methylglyoxal inactivates the enzyme (Glyceraldehyde-3-

Phosphate Dehydrogenase) needed for ATP production in cancer

cells and thereby starves them to death. Normal cells remain

unaffected. "

Manju ray said that chemists knew Methylglyoxal molecule for

about four decades and its anti-cancer effects in animals had

also been studied. " But surprisingly, no one bothered to

initiate further research leading to human trials, " she said.

The researchers said concern in some quarters about safety of

which showed that in combination with protective agent like

Ascorbic Acid and vitamins, the drug Methylglyoxal had no

major toxic effect. They said there was scope for further

enhancing the drug's efficacy.

> To whom it may concern within the cures for cancer group:

> Hi, I am writing from Lisbon, Portugal.

> I have joined this group today because I have a twin sister who has

> been diagnosed acute leukemia last December and, in order to be

> helpful any further to her, I need to find out more about this

> disease. She was at the time 7month pregnant (first baby) and upon a

> routine ecography she found out that her baby had died - she was sent

> immediatly to hospital where she was given blood transfusions, and

> medication that induced her, the following morning, to give birth to

> the dead baby without the possibility of an anesthesic...two hours

> later she underwent a mielogram (exam to the medula?) which confirmed

> the doctor's suspicion:acute leukemia, technical name " M 5 " . She

> stayed in hospital undergoing chemotherapy until last May, when she

> was informed that the disease seemed to be in remission. The medula

> transplant was not then considered a possibility as, unfortunately,

> none of us five brothers and sisters have compatible medulas (not

> even myself as her twin..) and using a medula from a donor outside

> the family was considered too risky in her case. She stayed out of

> the hospital until the 2nd of September, when, unexpectedly, the

> disease stroke back again. Ever since, she has underwent a High

> Density Chemotherapy which has not proved to be effective,

> unfortunately... As she has been feeling very depressed lately

> because her blood values are persistently low, last Wednesday she was

> exceptionally allowed to leave for a few days, having to stay home

> and taking lots of precautions to prevent any sort of infections -

> because next Monday she will start a second cycle of High density

> Chemotherapy - hoping that it will be effective this time!

> Her supervising doctor is considered an expert on the disease in

> Portugal, but on human terms she is someone difficult to approach -

> so, I wonder wether in this egroup there may be someone who might

> help me to find out more about the disease and, also, if there are

> any alternative sources of relief - compatible with the current chemo

> treatment prescribed - that may help her in this tough struggle.

> I apreciate the solidarity implied in this egroup and any possibly-

> helpful reply.

> All the best, Gubi

>

>

>

>

> Get HUGE info at http://www.cures for cancer.ws, and post your own links there.

Unsubscribe by sending email to cures for cancer-unsubscribeegroups or by

visiting http://www.bobhurt.com/subunsub.mv

>

>

[Guest guest]

From: " gubi6363 " <gubi6363@...>

<cures for cancer >

Sent: Friday, October 10, 2003 11:05 AM

Subject: Twin Sister with Acute Leukemia

Hi,

this isn't medical advice, just some things to follow up on.........

1: Br J Haematol 2002 Mar;116(3):555-63

Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia

myeloid cell lines: induction of apoptosis and inhibition of proliferation.

Rojewski MT, Baldus C, Knauf W, Thiel E, Schrezenmeier H.

Freie Universitat Berlin, Universitatsklinikum lin, Medizinische

Klinik III (Hamatologie, Onkologie und Transfusionsmedizin), Berlin, Germany.

Clinical efficacy of As2O3 has been shown in patients with relapsed acute

promyelocytic leukaemia (APL). There is evidence that the effects of As2O3 are

not restricted to events specific for APL. As2O3 might target mechanisms

involved in the pathogenesis of other malignancies. We assessed susceptibility

to induction of apoptosis by As2O3 and cytostatics in 22 myeloid and non-myeloid

malignant cell lines. As2O3 was used in concentrations of 0center dot01--10

micromol/l. Cell lines displayed different kinetics of response and different

sensitivity to As2O3. The minimum concentration of As2O3 for induction of

apoptosis was 0center dot1 micromol/l. High concentrations of As2O3 (5

micromol/l) induced apoptosis in a large proportion of cells in all cell lines

tested. Low (1 micromol/l As2O3) concentrations induced apoptosis in NB-4,

HL-60, U-937, CEM, HL-60, KG-1a, PBL-985, ML-2 and MV-4--11, but not in HEL,

K-562, KG-1 and Jurkat up to 35 d of incubation. However, the non-apoptotic

population of 1 micromol/l As2O3-treated HEL, K-562, K-562 (0center dot02),

K-562(0center dot1) and Jurkat showed reduced proliferation. CEM as well as its'

multidrug-resistant derivatives were sensitive to 1 micromol/l As2O3. In

summary, these data demonstrate that As2O3-induced apoptosis is not restricted

to cell lines with t(15;17). Apoptosis was induced in vitro by As2O3

concentrations that are achievable in vivo after infusion of well-tolerated

As2O3 doses. Thus, As2O3 might be a suitable therapeutic agent for malignancies

other than APL provided the adequate dose and duration of As2O3 treatment are

used.

PMID: 11849211 [PubMed - in process]

2: Chin Med J (Engl) 2000 Jun;113(6):498-501

[Potentiation of arsenic trioxide-induced apoptosis by retinoic acid in retinoic

acid sensitive and resistant HL-60 myeloid leukemia cells]

[Article in Chinese]

Huang X.

Institute of Hematology, People's Hospital, Beijing Medical University, Beijing

100044, China.

OBJECTIVE: To study the effect of arsenic trioxide (As2O3) on non-APL acute

myeloid leukemia (AML) cells and the interreactive effect between retinoic acid

(RA) and As2O3. METHODS: RA-sensitive (S) and RA-resistant ® HL-60 non-APL AML

cells were used as an in vitro model. Cell number and trypan blue were used to

observe cell growth and survival. Apoptosis was determined by morphological

changes, using a DNA laddering assay, terminal deoxynucleotidyl transferase

(TdT) fragment end labeling assay and a flow cytometry assay. RESULTS: As2O3

induced apoptosis in both HL-60S and HL-60R cells, As2O3-induced apoptosis was

both time- and concentration-dependent in a therapeutically-achievable As2O3

range (0.25-4.0 mumol/L). Both all-trans retinoic acid (ATRA) and 9-cis retinoic

acid (9cRA) potentiated As2O3-induced apoptosis, as measured by quantitative TdT

fragment and labeling and flow cytometry assays in both HL-60S and HL-60R cells

(P < 0.05, for all RA + As2O3 combinations vs As2O3 alone in both sublines).

CONCLUSIONS: As2O3 may inhibit the growth of non-APL AML cells by promoting

programmed cell death. RA can potentiate As2O3-induced apoptosis even in

RA-resistant HL-60 cells in which the classical ATRA response pathway is

repressed owing to a homozygous inactivating mutation in the retinoic acid

receptor alpha. As2O3 can have clinical activity in non-APL cases of AML and the

enhanced activity might result from the combined As2O3-RA therapy.

PMID: 11775865 [PubMed - indexed for MEDLINE]

3: Br J Haematol 2001 Mar;112(3):783-6

Arsenic trioxide and ascorbic acid: synergy with potential implications for the

treatment of acute myeloid leukaemia?

Bachleitner-Hofmann T, Gisslinger B, Grumbeck E, Gisslinger H.

Department of Internal Medicine I, Division of Haematology and Blood

Coagulation, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna,

Austria.

Arsenic trioxide (As2O3) induces remission in a high proportion of patients with

acute promyelocytic leukaemia (APL) via induction of apoptosis. Preliminary

reports suggest that the apoptotic effect of As2O3 is not specific for APL but

can also be observed in non-APL acute myeloid leukaemia (AML) cells, although

these are less sensitive than APL cells. Ascorbic acid has recently been

demonstrated to enhance the apoptotic effect of As2O3. We have therefore

evaluated combined As2O3/ascorbic acid treatment in various clinical samples of

AML. Our results indicate a significant synergistic effect of As2O3 and ascorbic

acid, suggesting a possible future role of As2O3/ascorbic acid combination

therapy in patients with AML.

Publication Types:

Evaluation Studies

PMID: 11260084 [PubMed - indexed for MEDLINE]

4: Blood 2000 Feb 1;95(3):1014-22

Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells

that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-x(L).

Perkins C, Kim CN, Fang G, Bhalla KN.

Division of Clinical and Translational Research, Sylvester Comprehensive Cancer

Center, University of Miami School of Medicine, Miami, FL 33136, USA.

We investigated the in vitro growth inhibitory and apoptotic effects of

clinically achievable concentrations of As(2)O(3) (0.5 to 2.0 micromol/L)

against human myeloid leukemia cells known to be resistant to a number of

apoptotic stimuli. These included chronic myelocytic leukemia (CML) blast crisis

K562 and HL-60/Bcr-Abl cells, which contain p210 and p185 Bcr-Abl, respectively,

and HL-60 cell types that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-x(L)

(HL-60/Bcl-x(L)), MDR (HL-60/VCR), or MRP (HL-60/AR) protein. The

growth-inhibitory IC(50) values for As(2)O(3) treatment for 7 days against all

these cell types ranged from 0.8 to 1.5 micromol/L. Exposure to 2 micromol/L

As(2)O(3) for 7 days induced apoptosis of all cell types, including

HL-60/Bcr-Abl and K562 cells. This was associated with the cytosolic

accumulation of cyt c and preapoptotic mitochondrial events, such as the loss of

inner membrane potential (DeltaPsim) and the increase in reactive oxygen species

(ROS). Treatment with As(2)O(3) (2 micromol/L) generated the activities of

caspases, which produced the cleavage of the BH3 domain containing proapoptotic

Bid protein and poly (ADP-ribose) polymerase. Significantly, As(2)O(3)-induced

apoptosis of HL-60/Bcr-Abl and K562 cells was associated with a decline in

Bcr-Abl protein levels, without any significant alterations in the levels of

Bcl-x(L), Bax, Apaf-1, Fas, and FasL. Although As(2)O(3 )treatment caused a

marked increase in the expression of the myeloid differentiation marker CD11b,

it did not affect Hb levels in HL-60/Bcr-Abl, K562, or HL-60/neo cells. However,

in these cells, As(2)O(3 )potently induced hyper-acetylation of the histones H3

and H4. These findings characterize As(2)O(3) as a growth inhibiting and

apoptosis-inducing agent against a variety of myeloid leukemia cells resistant

to multiple apoptotic stimuli.

PMID: 10648417 [PubMed - indexed for MEDLINE]

5: Med Oncol 1999 Apr;16(1):58-64

Arsenic trioxide induces apoptosis of myeloid leukemia cells by activation of

caspases.

Huang XJ, Wiernik PH, Klein RS, Gallagher RE.

Department of Oncology, Montefiore Medical Center, The Albert Einstein Cancer

Center, Bronx, NY 10467, USA.

The primary objective of this study was to determine whether caspases are

involved in arsenic trioxide(ATO)-induced apoptosis of human myeloid leukemia

cells. A secondary objective was to determine whether apoptosis induced by ATO

compared with VP-16 is differentially affected by an activator of protein kinase

C (PKC), phorbol 12-myristate 13-acetate (PMA), which has been reported to

inhibit apoptosis induced by some chemotherapeutic agents. NB4 and HL60 cells

were incubated with ATO in the presence and absence of the caspase protease

inhibitors Z-VAD.fmk or Y-VAD.cho. Apoptosis was assessed by morphology, DNA

laddering and flow cytometry. Poly (ADP-ribose) polymerase (PARP) cleavage was

used as a marker for the activation of caspases. PARP cleavage occurred during

ATO-induced apoptosis in both NB4 and HL60 cells. Z-VAD.fmk, a broad-spectrum

inhibitor, could block ATO-induced apoptosis and PARP cleavage, whilst

Y-VAD.cho, a selective inhibitor of caspase 1, had no such effect. PMA

pre-incubation for up to 8 hours under conditions known to activate PKC had no

effect on either ATO- or VP-16-induced apoptosis. We conclude that in cultured

myeloid leukemia cells ATO-induced apoptosis is executed by caspases from the

distal, PARP-cleaving part of the activation cascade and that PKC activation has

no effect on apoptosis induced by either ATO or VP-16 in these cells.

PMID: 10382944 [PubMed - indexed for MEDLINE]

6: Cancer Res 1999 Feb 15;59(4):776-80

Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells.

Li YM, Broome JD.

Department of Laboratories, North Shore University Hospital, Manhasset, New York

11030, USA. YMLI@...

Arsenic exhibits a differential toxicity to cancer cells. At a high

concentration (>5 microM), As2O3 causes acute necrosis in various cell lines. At

a lower concentration (0.5-5 microm), it induces myeloid cell maturation and an

arrest in metaphase, leading to apoptosis. As2O3-treated cells have features

found with both tubulin-assembling enhancers (Taxol) and inhibitors

(colchicine). Prior treatment of monomeric tubulin with As2O3 markedly inhibits

GTP-induced polymerization and microtubule formation in vitro but does not

destabilize GTP-induced tubulin polymers. Cross-inhibition experiments indicate

that As2O3 is a noncompetitive inhibitor of GTP binding to tubulin. These

observations correlate with the three-dimensional structure of beta-tubulin and

suggest that the cross-linking of two vicinal cysteine residues (Cys-12 and

Cys-213) by trivalent arsenic inactivates the GTP binding site. Furthermore,

exogenous GTP can prevent As2O3-induced mitotic arrest.

PMID: 10029061 [PubMed - indexed for MEDLINE]

7: Blood 1998 Sep 1;92(5):1497-504

Arsenic trioxide and melarsoprol induce programmed cell death in myeloid

leukemia cell lines and function in a PML and PML-RARalpha independent manner.

Wang ZG, Rivi R, Delva L, Konig A, Scheinberg DA, Gambacorti-Passerini C,

Gabrilove JL, Warrell RP Jr, Pandolfi PP.

Department of Human Genetics, Molecular Biology Program, and the Molecular

Therapeutics Program, the Sloan-Kettering Institute, Graduate School of Medical

Sciences, Cornell University, New York, NY, 10021, USA.

Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were

recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic

leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has

been proposed to principally target PML and PML-RARalpha proteins in APL cells.

We investigated the activity of As2O3 and melarsoprol in a broader context

encompassing various myeloid leukemia cell lines, including the APL cell line

NB4-306 (a retinoic acid-resistant cell line derived from NB4 that no longer

expresses the intact PML-RARalpha fusion protein), HL60, KG-1, and the

myelomonocytic cell line U937. To examine the role of PML in mediating arsenical

activity, we also tested these agents using murine embryonic fibroblasts (MEFs)

and bone marrow (BM) progenitors in which the PML gene had been inactivated by

homologous recombination. Unexpectedly, we found that both compounds inhibited

cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell

lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations

ranging from 10(-7) to 10(-5) mol/L. As2O3 relocalized PML and PML-RARalpha onto

nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60

and U937 cell lines. Although melarsoprol was more potent in inhibiting growth

and inducing apoptosis, it did not affect PML and/or PML-RARalpha nuclear

localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth

and induced apoptosis of PML+/+ and PML-/- MEFs, and inhibited colony-forming

unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of

PML+/+ and PML-/- progenitors. Together, these results show that As2O3 and

melarsoprol inhibit growth and induce apoptosis independent of both PML and

PML-RARalpha expression in a variety of myeloid leukemia cell lines, and suggest

that these agents may be more broadly used for treatment of leukemias other than

APL. Copyright 1998 by The American Society of Hematology.

PMID: 9716575 [PubMed - indexed for MEDLINE]

Curcumin as an inhibitor of cancer.

J Am Coll Nutr, 64(2):192-8 1992 Apr

Curcumin I (Cur I) and curcumin III (Cur III) are the

yellow coloring phenolic compounds isolated from the spice

turmeric. The effect of curcumins on different stages of

development of cancer was studied. Cur I inhibited

benzopyrene- (BP) induced forestomach tumors in female

Swiss mice, and Cur III inhibited dimethylbenzanthracene-

(DMBA) induced skin tumors in Swiss bald mice. Cur I also

inhibited DMBA-initiated, tetradeconyl phorbol

acetate-promoted skin tumors in female Swiss mice. In

vitro 3H-BP-DNA interaction studies, and in vivo

carcinogen metabolizing enzyme studies revealed that

curcumins exert anticarcinogenic activity by altering the

activation and/or detoxification process of carcinogen

metabolism. Cur I and Cur III also exhibit in vitro

cytotoxicity against human chronic myeloid leukemia, which

is dose dependent. This study shows that curcumins inhibit

cancer at initiation, promotion and progression stages of

development.

Sponsor: Blood Online is sponsor

* Li, Y. M., Broome, J. D. (1999). Arsenic Targets Tubulins to Induce

Apoptosis in Myeloid Leukemia Cells. Cancer Res 59: 776-780

[Abstract] [Full Text]

C., Gabrilove, J. L., Warrell, R. P. Jr, Pandolfi, P. P. (1998).

Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in

Myeloid Leukemia Cell Lines and Function in a PML and PML-RARalpha

Independent Manner. Blood 92: 1497-1504 [Abstract] [Full Text]

1: Cancer Chemother Pharmacol 1999;44(5):417-21

Clinical study of an organic arsenical, melarsoprol, in patients with advanced

leukemia.

Soignet SL, Tong WP, Hirschfeld S, Warrell RP Jr.

Developmental Chemotherapy, Department of Medicine, Memorial Sloan-Kettering

Cancer Center, Cornell University Medical College, 1275 York Avenue, New York,

NY 10021, USA. soignets@...

Inorganic arsenic trioxide (As(2)O(3)) induces a high proportion of complete

remissions in relapsed patients with acute promyelocytic leukemia (APL).

Previously, we have shown that both As(2)O(3 )and melarsoprol, an organic

arsenical used for the treatment of trypanosomiasis, exhibit broad antileukemic

activity against both chronic and acute myeloid and lymphoid leukemia cell

lines. Given the breadth of this activity, we initiated a clinical study to

evaluate the pharmacokinetics, safety, and potential efficacy of melarsoprol in

patients with refractory or resistant leukemia. Using the antitrypanosomal dose

and schedule, patients received escalating intravenous doses daily for 3 days,

repeated weekly for 3 weeks. Doses were 1 mg/kg on day 1, 2 mg/kg on day 2, and

3.6 mg/kg on day 3 and on all days thereafter, up to a maximum daily dose of 200

mg. Eight patients [6 AML (2 morphologic APL), 1 CML, 1 CLL] were treated. Mean

peak plasma concentrations of the parent drug were obtained immediately after

injection, ranged from 1.2 microg/ml on day 1 to 2.4 microg/ml on day 3, were

dose proportional, and decayed with a t(1/2) congruent with 15 min. A minor

clinical response (regression of splenomegaly and lymphadenopathy) was observed

in a patient with chronic lymphocytic leukemia. Central nervous system (CNS)

toxicity proved limiting on this dose and schedule. Three patients experienced

generalized grand mal seizures during the second week of therapy. We concluded

that this dose and schedule of melarsoprol is associated with excessive CNS

toxicity and that verification of the striking preclinical activity in patients

with leukemia will require developing an alternative dose and schedule.

Publication Types:

Clinical Trial

Clinical Trial, Phase I

Multicenter Study

PMID: 10501916 [PubMed - indexed for MEDLINE]

1: Blood Rev 1997 Mar;11(1):39-45

High-dose cytosine arabinoside in the treatment of acute myeloid leukaemia.

Cole N, Gibson BE.

Department of Haematology, Royal Hospital for Sick Children, Glasgow, UK.

Cytosine arabinoside (Ara-C) has earned its recognition as the most important

antileukaemic drug currently available for the treatment of acute myeloid

leukaemia. Approximately 60-80% of patients less than 60 years of age can be

expected to enter complete remission if treated with standard-dose Ara-C

(100-200 mg/m2) in combination with an anthracycline. The efficacy of Ara-C

appears clinically to be dose and schedule dependent. A 15-30 fold dose

escalation in Ara-C can elicit a therapeutic response in patients who have

previously failed treatment with standard-dose Ara-C or other anti-leukaemic

drugs. The use of high-dose cytosine arabinoside (HDAC 3 gm/m2) appears rational

based on cytosine pharmacology. Drug-scheduling is used to exploit drug synergy

when HDAC is given in combination with asparaginase or fludarabine (+/- G-CSF)

in a schedule-dependent fashion. Toxicity following Ara-C is also dose- and

schedule-dependent. Central nervous system toxicity--particularly cerebellar

dysfunction--although rare, is particularly serious because it may preclude

further use of the drug. Older patients are particularly susceptible. This

article will describe the rationale for and the value of HDAC alone or in

combination with other cytotoxics in the treatment of acute myeloid leukaemia.

[Hindustan Times]

Last updated 22:00 IST | Monday, May 28, 2001, New Delhi

Has the ultimate cancer cure arrived?

(Hyderabaad, May 28)

INDIAN CANCER researchers have taken a giant step on the road

to discovering the ultimate cancer cure by developing a drug

that selectively targets the cancer cells without harming the healthy ones.

Researchers in Kolkata claim that patients in " very advanced

stages " of cancer for whom all other treatments had failed

have been brought back to " excellent " health with the help of Others....

a drug formulation they have developed after research

spanning more than a decade.

" We have what we think magic bullet against cancer, " says

Cultivation of Science (IACS) where the drug was developed

under a project funded by the Department of Science and

Technology and the Council of Scientific and Industrial

bail

Most currently available anti-cancer drugs are toxic because

they also damage the normal cells. Ray says the IACS

formulation, containing " Methylglyoxal " as the lead

ingredient, combats only the diseased cells, the cherished

goal of cancer researchers worldwide. Methylglyoxal is a

metabolite in the human body produced during glucose

breakdown.

Others involved in the project are Swapna Ghosh of IACS,

Manoj Kar and Subhankar Ray of the University College of

Science, and Santajit Datta, a medical practitioner. Results

of human trial conducted by them with the new drug have

recently appeared in the Indian Journal of Physics.

While Americans are going ga-ga with their new anti-cancer

drug " Glivec " - that was featured on the cover of May 28

issue of Time magazine - the low-profile, cash-strapped

Kolkata researchers have been working quietly for over a

decade shunning publicity until they obtained proof from

human trials nine weeks ago.

According to their published paper, the Methylglyoxal-based

forumulation had " a dramatic positive effect on the

patients " .

For instance, the condition of 11 out of the 19 patients

treated - most of them in a very advanced stage when the

treatment began -- are now stated to be in " excellent

physical condition " . Five are in stable condition and only

three died during the course of the study.

Since the submission of the paper, the number of patients

treated has crossed 40 mark with more than 70 per cent

success, according to Manju Ray.

Most remarkable fact, according to the scientists was that

Methylglyoxal was successful against different types of

cancer unlike " Glivec " which targets only the chronic myeloid

leukemia.

Those whose health returned to " excellent " condition after

treatment with Methylglyoxal included patients in " a very

advanced stages " of colon cancer, acute myeloid leukemia,

non-Hodgkin's lymphoma, and cancers of ovary, breast, liver,

lung, bone, gall bladder, pancreas and oral cavity.

The patients were inducted for the trial, from January to

June 2000, after obtaining permission from the Drug

Controller General of India, the scientists said. The drug

was administered orally for about six months with gradual

reduction of daily dosage from the initial 25 milligrams per

kilogram of body weight.

refuses formal

Researchers said development of the drug was preceded by

years of basic research involving human cancer cells in

culture and animal experiments that showed that Methylglyoxal

* selectively killed the cancer cells without affecting normal

cells by exploiting " a very significant " biochemical

difference between the two.

Explaining the mechanism of action, the scientists said

cancer cells required a large amount of energy providing

substance called ATP (Adenosine-5-Triphosphate) for survival.

" Methylglyoxal inactivates the enzyme (Glyceraldehyde-3-

Phosphate Dehydrogenase) needed for ATP production in cancer

cells and thereby starves them to death. Normal cells remain

unaffected. "

Manju ray said that chemists knew Methylglyoxal molecule for

about four decades and its anti-cancer effects in animals had

also been studied. " But surprisingly, no one bothered to

initiate further research leading to human trials, " she said.

The researchers said concern in some quarters about safety of

which showed that in combination with protective agent like

Ascorbic Acid and vitamins, the drug Methylglyoxal had no

major toxic effect. They said there was scope for further

enhancing the drug's efficacy.

> To whom it may concern within the cures for cancer group:

> Hi, I am writing from Lisbon, Portugal.

> I have joined this group today because I have a twin sister who has

> been diagnosed acute leukemia last December and, in order to be

> helpful any further to her, I need to find out more about this

> disease. She was at the time 7month pregnant (first baby) and upon a

> routine ecography she found out that her baby had died - she was sent

> immediatly to hospital where she was given blood transfusions, and

> medication that induced her, the following morning, to give birth to

> the dead baby without the possibility of an anesthesic...two hours

> later she underwent a mielogram (exam to the medula?) which confirmed

> the doctor's suspicion:acute leukemia, technical name " M 5 " . She

> stayed in hospital undergoing chemotherapy until last May, when she

> was informed that the disease seemed to be in remission. The medula

> transplant was not then considered a possibility as, unfortunately,

> none of us five brothers and sisters have compatible medulas (not

> even myself as her twin..) and using a medula from a donor outside

> the family was considered too risky in her case. She stayed out of

> the hospital until the 2nd of September, when, unexpectedly, the

> disease stroke back again. Ever since, she has underwent a High

> Density Chemotherapy which has not proved to be effective,

> unfortunately... As she has been feeling very depressed lately

> because her blood values are persistently low, last Wednesday she was

> exceptionally allowed to leave for a few days, having to stay home

> and taking lots of precautions to prevent any sort of infections -

> because next Monday she will start a second cycle of High density

> Chemotherapy - hoping that it will be effective this time!

> Her supervising doctor is considered an expert on the disease in

> Portugal, but on human terms she is someone difficult to approach -

> so, I wonder wether in this egroup there may be someone who might

> help me to find out more about the disease and, also, if there are

> any alternative sources of relief - compatible with the current chemo

> treatment prescribed - that may help her in this tough struggle.

> I apreciate the solidarity implied in this egroup and any possibly-

> helpful reply.

> All the best, Gubi

>

>

>

>

> Get HUGE info at http://www.cures for cancer.ws, and post your own links there.

Unsubscribe by sending email to cures for cancer-unsubscribeegroups or by

visiting http://www.bobhurt.com/subunsub.mv

>

>

[Guest guest]

Moonbeam,

The research on arsenic and arsenite vs AML is very sketchy and almost

all in vitro. I have cautiously tried various combinations that have

included arsenic but I don't recommend it until certain questions are

answered: e.g.:

****************************************************************************

*******

Blood. 2001 Jul 15;98(2):266-71.

Sudden death among patients with acute promyelocytic leukemia treated with

arsenic trioxide.

Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, Luger SM, Ma

MK, Ley TJ, DiPersio JF.

Division of Bone Marrow Transplantation and Stem Cell Biology, and the

Division of Molecular Oncology, Washington University School of Medicine, St

Louis, MO 63110, USA.

Arsenic trioxide has been shown to be effective in treating acute

promyelocytic leukemia (APL), with minimal overall toxicity reported to

date. A phase I/II study was initiated in June 1998 using arsenic trioxide

for relapsed APL to determine the maximum tolerated or minimal effective

dose and to determine the efficacy of treatment at that dose. Ten patients

received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day

intravenous arsenic trioxide. Six of 7 patients evaluable for response

achieved cytogenetic or molecular complete remission. However, 3 patients

died suddenly during the first cycle of treatment. Autopsies obtained on 2

of these failed to identify a cause of sudden death, despite evidence of

pulmonary hemorrhage in one. A third patient, for whom an autopsy was not

performed, became asystolic and died while on continuous cardiac telemetry.

These observations suggest that arsenic trioxide may be significantly or

even fatally toxic at doses currently used and that caution is warranted in

its use.

****************************************************************************

*************

Very few people in Portugal have access to the best alternative

medicine has to offer. They pretty much have to take matters completely

into their own hands. There is no cheaper source of arsenic than brake fern

and I have seen it grow wild in France. Fowler's solution is very easy to

make for those so inclined. Arsenic does put the kibosh on DNA repair

mechanisms though. Patients do build up a tolerance to arsenic very

quickly.

I have used a fair amount of methylglyoxal but have never seen it work

on a patient in blast crisis. I do think that methylglyoxal is safe in the

dosages that Manju Ray recommends. I have seen patients take considerably

higher amounts without ill effect.

Curcumin can be a helpful strategy but it must be consistent with the

rest of one's plan. It can diminish the usefulness of certain other drugs.

I often use curcumin as part of the follow-up strategy after the tumor load

is reduced by other means.

[Guest guest]

Moonbeam,

The research on arsenic and arsenite vs AML is very sketchy and almost

all in vitro. I have cautiously tried various combinations that have

included arsenic but I don't recommend it until certain questions are

answered: e.g.:

****************************************************************************

*******

Blood. 2001 Jul 15;98(2):266-71.

Sudden death among patients with acute promyelocytic leukemia treated with

arsenic trioxide.

Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, Luger SM, Ma

MK, Ley TJ, DiPersio JF.

Division of Bone Marrow Transplantation and Stem Cell Biology, and the

Division of Molecular Oncology, Washington University School of Medicine, St

Louis, MO 63110, USA.

Arsenic trioxide has been shown to be effective in treating acute

promyelocytic leukemia (APL), with minimal overall toxicity reported to

date. A phase I/II study was initiated in June 1998 using arsenic trioxide

for relapsed APL to determine the maximum tolerated or minimal effective

dose and to determine the efficacy of treatment at that dose. Ten patients

received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day

intravenous arsenic trioxide. Six of 7 patients evaluable for response

achieved cytogenetic or molecular complete remission. However, 3 patients

died suddenly during the first cycle of treatment. Autopsies obtained on 2

of these failed to identify a cause of sudden death, despite evidence of

pulmonary hemorrhage in one. A third patient, for whom an autopsy was not

performed, became asystolic and died while on continuous cardiac telemetry.

These observations suggest that arsenic trioxide may be significantly or

even fatally toxic at doses currently used and that caution is warranted in

its use.

****************************************************************************

*************

Very few people in Portugal have access to the best alternative

medicine has to offer. They pretty much have to take matters completely

into their own hands. There is no cheaper source of arsenic than brake fern

and I have seen it grow wild in France. Fowler's solution is very easy to

make for those so inclined. Arsenic does put the kibosh on DNA repair

mechanisms though. Patients do build up a tolerance to arsenic very

quickly.

I have used a fair amount of methylglyoxal but have never seen it work

on a patient in blast crisis. I do think that methylglyoxal is safe in the

dosages that Manju Ray recommends. I have seen patients take considerably

higher amounts without ill effect.

Curcumin can be a helpful strategy but it must be consistent with the

rest of one's plan. It can diminish the usefulness of certain other drugs.

I often use curcumin as part of the follow-up strategy after the tumor load

is reduced by other means.

[Guest guest]

In China, the use of arsenic to treat leukemia dates back more than

two thousand years, and more recently, to the early 70s, when

hospitals in that country started combining this traditional remedy

(alone or with herbal components) with " mainstream Western " treatments

(the way it is often done there, still in accordance with Chairman

Mao's medical paradigm -- a wiser one than ours -- that went something

like, " We don't care if it's a black cat or a white cat long as it

catches mice. " )

Here's a link that might provide some useful answers (e.g., how to

counteract arsenic's toxicity):

http://alternativehealing.org/chronic_myelogenous_leukemia.htm

I've also seen a Chinese article stating that metylated metabolites of

arsenic trioxide are much more efficient than arsenic trioxide; I

think they were talking about in vivo results, but I'm not entirely sure.

Elena

[Guest guest]

In China, the use of arsenic to treat leukemia dates back more than

two thousand years, and more recently, to the early 70s, when

hospitals in that country started combining this traditional remedy

(alone or with herbal components) with " mainstream Western " treatments

(the way it is often done there, still in accordance with Chairman

Mao's medical paradigm -- a wiser one than ours -- that went something

like, " We don't care if it's a black cat or a white cat long as it

catches mice. " )

Here's a link that might provide some useful answers (e.g., how to

counteract arsenic's toxicity):

http://alternativehealing.org/chronic_myelogenous_leukemia.htm

I've also seen a Chinese article stating that metylated metabolites of

arsenic trioxide are much more efficient than arsenic trioxide; I

think they were talking about in vivo results, but I'm not entirely sure.

Elena