Vinblastine for

Cells that exhibit high (several hundredfold) levels of resistance to vinblastine, vincristine, and vindesine have an extremely limited capacity to accumulate radiolabeled vinblastine for example, essentially no increase in radioactivity associated with human leukemic lymphoblastic cells resistant to vinblastine could be detected over a 60-min incubation period in the presence of concentrations of tritiated vinblastine that were cytotoxic to parent cells. The parent cells, highly sensitive to vinblastine, were observed to accumulate vinblastine to levels seven-fold higher than those observed for the resistant cells (76). 

The absorption of some drugs may be reduced due to damage of the small intestine. This is most likely after cytotoxic therapy. The absorption of phenytoin and verapamil can be reduced by 20-35% in patients taking cytotoxic drugs such as methotrexate, carmustine, or vinblastine for the treatment of malignant disease. The reduced absorption was accompanied by evidence of loss of therapeutic effect. 

Most of the transformations carried out on catharanthine have naturally been concerned with the preparation of potential precursors of dimeric bases related to vinblastine. For example, 15-acetoxydihydrocatharanthine (configuration at C-15 unknown) is also obtained, together with the recently reported221 20-acetoxydi-hydrocatharanthine, when catharanthine is subjected to the modified Prevost reaction.139 The conversion of catharanthine (236) into the potentially useful epoxides (237a), (237b), and (239), the lactone (238), and the diol (240) (stereochemistry at C-15 and C-20 not rigorously proved) has also been described (Scheme 25).140,141... 

Although many other alkaloids have been isolated from C. roseus only vinblastine and vincristine have been developed for clinical use. The antiproliferative activity of the two compounds is related to their specific interaction with tubulin, thus preventing assembly of tubulin into microtubules and arresting cell division (59). However, despite this apparent identical mechanism of action and their clear chemical similarities, vinblastine and vincristine display very different clinical effects. Vinblastine, for example, is used to treat Hodgkin s disease and metastatic testicular tumors, whereas vincristine is used mainly in combination with other anticancer drugs for the treatment of acute lymphocyticleukemia in children. Toxicity profiles are also different, in that vinblastine causes bone-marrow depression, whereas peripheral neuropathy often proves to be dose-limiting in vincristine therapy. 

Rednced peripheral circnlation, Raynaud s phenomenon, and polynenropathy have been described after the combined nse of cisplatin, bleomycin, and vinblastine for testicnlar tnmors. Of eight cases with polyneuropathy that were investigated, it was not possible to confirm a cansa-tive association between Rajmand s phenomenon and the chemotherapy (52). 

Despite only a minor difference in the chemical structures of vinblastine and vincristine, the clinical effects differ considerably. Surprisingly there is no clinical evidence of cross resistance between them, or with radiation and other presently known oncolytic agents. The rise and fall of the blood activity level of vincristine is steeper than that of vinblastine.The dosage requirements of both alkaloids differ markedly the weekly intravenous dose of vinblastine for humans is 0.1—0.2 mg per kg, that of vincristine, however, is approximately one tenth of this. Concerning the side-effects, vincristine shows more neurotoxic effects and vinblastine is considered to have more potency in bone-marrow depression. This is not without consequences on human therapy therapy is limited by bone-marrow depression with vinblastine and neuromuscular effects, with vincristine. Early symptoms of side-effects are vomiting, fever, and exanthemes. Late symptoms are C.N.S. disturbances, alopecia, and leukopenia. C.N.S. disturbances are manifested by various symptoms such as paresthesias, neuritis, paresis, and muscular atrophy, accompanied by quenched reflexes. Even behaviour may be affected after a long period of treatment. But why do all these side-effects happen, when Vinca alkaloids are unable to pass the blood-brain barrier The only explanation we have at hand is that they are possibly caused by metabolites or breakdown products of the normal biochemical pathways, which are disturbed by the alkaloids. 

Velocity sedimentation profiles of tubulin have been numerically simulated to elucidate the process of its self association induced by vinblastine. For a... 

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