AACR: Effective Leukemia, Lymphoma Treatment May Require Survival Neutralizer

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AACR Abstract Number:

Drug-induced Apoptosis in Primary Malignant Lymphocytes

Dennis A. Carson. Univ. of California, San Diego, La Jolla, CA.

In many cancers, only a minor fraction of the malignant cells

actively divide during brief periods of exposure to chemotherapy.

Remission induction therefore requires the development of drugs that

kill both proliferating and quiescent tumor cells, while sparing most

normal cells.

Agents of this type are difficult to identify using established tumor

cell lines or transplantable murine tumors. Studies of drug induced

apoptosis in the easily accessible primary blood lymphocytes from

patients with chronic lymphocytic leukemia [CLL], hairy cell leukemia

[HCL] and other indolent malignancies, have provided leads to new

chemotherapeutic agents that were missed in traditional screening

systems. The most dramatic examples of the success of this approach

are the adenine deoxynucleosides cladribine, fludarabine, and

clofarabine, as well as the adenosine deaminase inhibitor

pentostatin.

The selective toxicity of these agents depends upon the unique

pattern of deoxyadenosine metabolism in interphase human lymphocytes.

These cells must rapidly accumulate purine deoxynucleotides for

synchronous DNA replication after exposure to a mitogenic stimulus.

Accordingly, they have a highly developed purine salvage pathway, as

measured by a high ratio of deoxyadenosine kinases to

nucleotidases/phosphatases compared to other cell types. Since cell

volume during interphase remains constant, blood lymphocytes exposed

to adenine deoxynucleosides progressively accumulate nucleotides

intracellularly, until a new equilibrium is reached or apoptosis

ensues. Each one of the deoxyadenosine analogs has distinct and

variable effects on a variety of enzymes involved in DNA repair, RNA

synthesis and energy metabolism. However, the exquisite sensitivity

of normal and malignant lymphocytes to these drugs probably depends

more on the kinetics of drug metabolism, rather than on a unique

biochemical target.

Both cladribine and pentostatin are highly effective in HCL, but

seldom induce complete remissions in CLL or lymphomas. This

discrepancy was difficult to explain until experiments revealed that

various soluble and adherent factors produced by normal cells in the

bone marrow and lymph nodes rendered CLL cells resistant to

spontaneous and drug induced apoptosis.

Effective treatment of resistant leukemias and lymphomas, and of many

solid tumors, may require the combination of a tumor-specific drug

with an agent that neutralizes survival factors produced by the

microenvironment.

Presenter: Dennis A. Carson.

Affiliation: Univ. of California, San Diego, La Jolla, CA

Copyright © 2004 American Association for Cancer Research. All rights

reserved. Citation information: Proceedings of the AACR, Volume 45,

March 2004.