VINCA ALKALOIDS - ANTIVASCULAR EFFECTS IN A MURINE TUMOR

We have investigated the blood flow modifying effects of the vinca alkaloids, vincristine and vinblastine in the murine carcinoma CaNT. Vinblastine at doses of 7.5 or 10 mg/kg induced profound and chronic reductions in tumour blood flow as measured by (RbCl)Rb-86 extraction. Following the maximum tolerated dose of 10 mg/kg, blood flow was reduced to 10% of pretreatment values after 2 h and remained below 20% of pretreatment values 24 h after drug administration. These findings are consistent with the early induction of necrosis by vinblastine and suggest that vascular-mediated cell death may account for a large part of the 11 day growth delay induced by this drug dose. In contrast to the large reductions in tumour blood flow, in skin, kidney, liver and muscle, blood flow reductions did not, at any time examined, exceed 40%. In all the normal tissues studied, blood flow had fully recovered by 6 h after vinblastine administration. Similar results, albeit less pronounced, have been obtained with vincristine at the maximum tolerated dose of 3 mg/kg. The results clearly show that both vinblastine and vincristine can induce, with some selectivity, a dramatic and prolonged reduction in tumour blood flow and that this may contribute to the anti-tumour effects against the CaNT tumour.