[Integrilin to prevent metastasis]
>>Platelets and metastasis revisited: a novel fatty link<<
jci.org
Ii the referenced post, I wondered about ML464, now see it is not ML<ital>N</ital>464. But the drug probably was Integrilin, and the above link -- which links to the underlying research paper -- follows up on the idea of antiplatelet therapy as a prophylactic for metastasis. Integerilin shows promise here, because unlike some others, it doesn't completely inhibit the homeostatic role of platelets, needed for normal function. Here's another reference in that area:
>>Thromb Haemost. 2003 Sep;90(3):549-54.
Inhibition of tumor cell-induced platelet aggregation and lung metastasis by the oral GpIIb/IIIa antagonist XV454.
Amirkhosravi A, Mousa SA, Amaya M, Blaydes S, Desai H, Meyer T, Francis JL.
Clinical and Research Laboratories, Florida Hospital Cancer Institute, 2501 N. Orange Ave, Suite 786, Orlando, Florida 32804, USA. ali.amirkhosravi@flhosp.org
Platelets are known to play a role in blood borne metastasis. Previous experimental studies have suggested that platelet GpIIb/IIIa may be a therapeutic target. However, the need for intravenous administration limits the potential application of current GpIIb/IIIa inhibitors to cancer therapy. The aim of the present study was to assess the efficacy of a novel, non-peptide oral GpIIb/IIIa antagonist (XV454) on tumor cell-induced platelet aggregation in vivo and on experimental metastasis. A Lewis lung carcinoma (LL2) mouse model of experimental metastasis was used in this study. XV454 (100 micro g) was administered intravenously (via tail vein) or orally (gavages) to 20 g mice. To determine the effect of XV454 on platelet aggregation, blood samples were collected by cardiac puncture 10 minutes after intravenous and 1-24 hrs after oral XV454, and platelet function was assessed by aggregometry, thrombelastography and the Platelet Function Analyzer (PFA100). The effect of XV454 on tumor cell-induced thrombocytopenia was determined 10 minutes after intravenous and 3 hrs after oral XV454 administration. Tumor cells (2 x 10(6)) were injected intravenously and 15 minutes after cell injection, platelet count was measured and compared to baseline (pre-injection) counts. To assess the effect on metastasis, XV454 was administered intravenous or orally 10 minutes and 3 hrs before tumor cell injection, respectively. Eighteen days later, surface lung tumor nodules were counted and the total lung tumor burden assessed. In a fourth group, in addition to the initial oral dose (before tumor cell injection), oral XV454 was given daily for the first week and three times in the second week. Administration of XV454 (5 mg/kg) completely inhibited platelet aggregation and this effect persisted for at least 24 hrs after oral delivery. Both intravenous and oral XV454 significantly inhibited tumor cell-induced thrombocytopenia (P < 0.01), the number of surface lung tumor nodules (80-85%; P < 0.001) and total tumor burden (83% for intravenous group; 50% oral [single treatment] group; 91% oral [multiple treatment] group, P < 0.001). Overall, these data provide further evidence for the effect of oral and intravenous GpIIb/IIIa antagonism on tumor cell-platelet interaction and metastasis.<<
Obviously, Integrilin and others like it could be superseded by a successful oral formulation, but those are in preclinical stages. XV454 was apparently developed by DuPont, whose pharmaceutical division was munched last year by BMS. Can't find mention of it from BMS, though, suggesting that, although being tested at DuPont in the late 90s, it has since languished.
Cheers, Tuck |
