The Vinca Alkaloids: a New Class of Oncolytic Agents.

A phytochemical investigation of the plant Vinca ro@eaLinn. has demonstrated that a number of alkaloidal substances can be obtained with antitumon activity. Over 30 alkaloids have been obtained, of which four—vinbiastine, vinleunosine, vincnistine, and vinrosidine—are known definitely to be active. Chemically these compounds are closely related to one another and to two monomeric alkaloids, vindoline and catharan thine. The structure of these latter two compounds has been determined, and partial structures for the biologically active alkaloids have been proposed. They represent a new class of large complex dimenic alkaloids containing both indole and dihydnoindole moieties. Experimentally, a strain-specific, transplantable, acute, lymphocytic leukemia (P-1534) carried in DBA/@mice served as a bioassay for obtaining these compounds and for predicting their clinical activity. Vinblastine, vincnistine, and vinrosidine are capable of prolonging and/on “curing― mice of the P-1534 leukemia even when therapy is delayed until a near-terminal state of generalized disease. Resistance to an additional challenge of leukemic cells has been observed in these “cured― animals. Parenteral ad ministration of vincnistine has been demonstrated to “cure― mice given intracranial implants of the P-1534. The experimental tumor spectrum and toxicological studies are presented and discussed. Biochemical studies performed to date do not reveal any effect on cellular nespira tion, glycolysis, protein or nucleic acid synthesis. The mechanisms of action of these compounds, which may differ within the group as well as from those of other known agents, remain to be determined. Only two of these compounds, vinbiastine and vincnistine, have received extensive clinical evaluation. In spite of their close similarity, chemically, a somewhat different group of human neoplasms responds to these compounds, and there has been a singular lack of cross-resistance between these two drugs and any other oncolytic drug now in wide use. Vinblastine has proved effective in chonioepithelioma, Hodgkin's disease, and other lymphomas, and a number of beneficial results have been obtained in car cinoma of the breast and bronchus. In addition, there have been smaller numbers of a variety of other neoplasias reported as responding to this compound. Vincnistine has been striking in its ability to induce complete hematological remission of the acute leukemias of childhood, both lymphocytic and myelogenous in type. Re sponses have also been reported in a number of other malignancies. The problems and obstacles encountered in obtaining a full realization of the clinical efficacy of these new types of oncolytic compounds are discussed in addition to areas of clinical application other than those previously reported.