Mitotic Inhibitors

Compounds known to inhibit the mitotic phase of the cell cycle offer potential usefulness in the treatment of cancer. Few such drugs, however, have reached clinical application either because of unacceptable toxicity or ineffectiveness. Two antimitotic agents are used for other purposes. The antibiotic griseofulvin is utilized for its antifungal properties. The alkaloid colchicine, although having antitumor activity, is used in the treatment of gout. Colchicine, obtained from the seeds of Colchicum autumnale, combines with tubulin reversibly. Tubulin is a protein, normally polymerizing to form microtubules found in animal and plant cells. Of particular interest is their function in chromosomal motion during mitosis. The ketonic area of the tropolone ring portion is the likely binding site. Inhibition of leukocyte microtubules is the probable reason for the alkaloid's strong antiinflammatory effect in gout. Podophyllotoxin, which is obtained from the resin of the May Apple or ch* ch-c* o

Thymine - 3 - propenal

Mandrake (Podophyllum peltatum) has been in use as a purgative and wart remover for centuries. The active antimitotic (metaphase) inhibition is believed to involve the lactone ring, which is in the trans configuration (Fig. 4-22). Epimerization to the cis form with alkali results in inactivity. Carcinolytic activity of the natural product is poor. However, some derivatives are more promising. Of particular interest is the epipodophyllotoxin glu-copyranoside derivative etoposide (VePesid, VP-16-213), which exhibits metaphase arrest. Microtubule synthesis is not affected. Etoposide is useful against refractory testicular tumors and small-cell lung carcinoma.

The periwinkle plant (Vinca rosa), which is indigenous to Florida, has yielded several indole alkaloids. Two with antineoplastic properties are the dimeric indole-dihydroindole derivatives vinblastine (VelbanĀ®) and vincristine (OncovinĀ®). These agents bind to tubulin, arresting mitosis at the metaphase.

Vincristine is effective against acute leukemia in children, frequently used to initiate a treatment that is then switched to more selective agents such as MTX or 6-MP. An alternate approach is to combine it with prednisone to effect a high percentage of complete remissions. Vinblastine, the more active compound, has had much wider clinical application, including solid tumors, especially in combination with such drugs as cisplatin and BLM (e.g., metastatic testicular cancer).

A new semisynthetic analog, 5-nor-anhydrovinblastine (Navelbine), is undergoing clinical trials and exhibits activity against non-small-cell lung cancer, breast and ovarian cancers, and Hodgkin's disease, with remission at 90% in the last. The chemical modification is shortening the distance from the upper (left) indole to the piperidine N on the right by one CH2 and dehydrating the tertiary alcohol to a double bond. Clinical tolerability is

Mitotic Inhibitors

Continue reading here: O

Was this article helpful?

0 0