IM may prevent/treat heart disease

[Guest guest]

Hey folks,

This isn't an ASH post, but rather, a really interesting letter to the

editor of the New England Journal of Medicine (reprinted below) that I just

happened to notice: through a rather complicated mechanism involving

inhibition of PDGFR, IM appears to reduce cholesterol and triglyceride

levels, and prevent the deposition of cholesterol into damaged arteries.

This is potentially really good news for CMLers on IM who also happen to

have or be at risk for coronary vascular disease. It's a heck of an

expensive way to bring your cholesterol down, but how nice to have a

positive side effect of the drug!

One sentence in the letter also jumped out at me? " both hypercholesterolemia

and hypertriglyceridemia were unmodified in the one patient whose condition

did not respond to the therapy. " To me this suggests that this patient had

inadequate uptake of IM either at the gut level or was metabolizing it

unusually fast, and that they'd benefit from an increased dose (or one of

the newer drugs). Once again, wouldn't it be nice to be able to check IM

serum levels?!

Cheers (and Happy New Year)

R

Imatinib and Hyperlipidemia

New England Journal of Medicine

Volume 353:2722-2723

December 22, 2005;Number 25

To the Editor: We report on a series of nine patients with hyperlipidemia

and either chronic myeloid leukemia or the hypereosinophilic syndrome, in

eight of whom plasma lipid levels normalized within one month after imatinib

therapy (at a dose of 400 mg daily) was started. All nine patients had

hypercholesterolemia (mean plasma total cholesterol level, 254 mg per

deciliter; range, 223 to 293); four of them also had hypertriglyceridemia

(mean plasma triglyceride level, 264 mg per deciliter; range, 230 to 368).

Patients who had concomitant diabetes mellitus, were currently consuming

alcohol, or were using oral contraception were excluded. Diet, weight, and

levels of physical activity remained unchanged during the course of imatinib

therapy. No patient received any drug known to affect lipid metabolism. The

normalization (estimated to occur 30 days after imatinib was started) of

cholesterolemia in eight of the nine patients (mean plasma total cholesterol

level, 176 mg per deciliter; range, 160 to 187) and of triglyceridemia in

three of four patients (mean plasma triglyceride level, 130 mg per

deciliter; range, 126 to 138) was persistent and long-lasting (median

follow-up, 20 months; range, 4 to 30). Both hypercholesterolemia and

hypertriglyceridemia were unmodified in the one patient whose condition did

not respond to the therapy (Table 1).

Imatinib mesylate (formerly STI571; now Gleevec in the UnitedStates and

Glivec in Europe [Novartis]) is a small molecule that has been shown to have

potent inhibitory activity against several tyrosine kinases, including ABL,

c-Kit, and the platelet-derived growth factor receptor (PDGFR), and has

become the primary target of therapy in chronic myeloid leukemia,

gastrointestinal stromal tumors, and the hypereosinophilic syndrome,

respectively.1 Tyrosine kinases are likely to play a pivotal role in the

pathogenesis of several diseases. In particular, PDGFR binds specifically to

and phosphorylates the cytoplasmic tail of the low-density lipoprotein

(LDL)-receptor­related protein (LRP),2 a member of the LDL-receptor

superfamily, which is known to act in areas as diverse as the degradation of

proteases, the activation of lysosomal enzymes, cholesterol metabolism, and

glucose-induced insulin secretion.3

Increasing evidence suggests that LRP is involved in cellular signaling in a

phosphorylation-dependent manner. Inhibition by imatinib of PDGFR-dependent

phosphorylation of the cytoplasmic domain of LRP has been shown to prevent

intimal hyperplasia after vascular injuries and fibrovascular proliferation

in mice with hypercholesterolemia.4 Moreover,

..5 Our observations suggest that in vivo modulation of the phosphorylation

pathway with the use of tyrosine kinase inhibitors may result in

modifications to lipoprotein metabolism that might be useful in the

prevention of atherosclerosis.

Michele Gottardi, M.D.

Ca' Foncello Hospital

31100 Treviso, Italy

michelegottardi@...

Enzo Manzato, M.D.

University of Padua

35128 Padua, Italy

Filippo Gherlinzoni, M.D.

Ca' Foncello Hospital

31100 Treviso, Italy

References

1. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer

therapy. N Engl J Med 2005;353:172-187. [Full Text]

2. Loukinova E, Ranganathan S, Kuznetsov S, et al. Platelet-derived

growth factor (PDGF)-induced tyrosine phosphorylation of the low density

lipoprotein receptor-related protein (LRP): evidence for integrated

co-receptor function between LRP and the PDGF. J Biol Chem

2002;277:15499-15506. [Abstract/Full Text]

3. Fujino T, Asaba H, Kang MJ, et al. Low-density lipoprotein

receptor-related protein 5 (LRP5) is essential for normal cholesterol

metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A

2003;100:229-234. [Abstract/Full Text]

4. Boucher P, Gotthardt M, Li WP, RG, Herz J. LRP: role in

vascular wall integrity and protection from atherosclerosis. Science

2003;300:329-332. [Abstract/Full Text]

5. Veneri D, Franchini M, Bonora E. Imatinib and regression of type 2

diabetes. N Engl J Med 2005;352:1049-1050. [Full Text]