Delayed toxicity of epipodophyllotoxin derivatives (VM 26 and VP 16-213), due to a local effect.
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The nature of G2-arrest was studied in Chinese hamster ovary cells after exposure to 4'-demethyl-epipodophyllotoxin 9-)4,6-0-2-thenylidene-beta-D-glycopyranoside (VM26), 1,3-bis(2-chloroethyl)-1-nitrosourea, 1,3-cis(2-chloroethyl)-1-nitrosourea, cis-4[[[(2-chloroethyl)-nitrosoamino] carbonyl] amino]- cyclohexane carboxylic acid, or neocarzinostatin. To determine whether this G2-arrest was due to a metabolic block or to damage to the genetic material, we employed the phenomenon of premature chromosome condensation to visualize the chromosomes of the G2-blocked cells by fusing them with mitotic cells. The prematurely condensed chromosomes (PCC) of the treated cells were scored for their position in the cell cycle and the extent of chromosomal damage in the G2-PCC. The data revealed a significant enrichment of the G2-fraction in all the treatments. Most of the G2- PCC from the treated cells were extensively damaged, showing 10 or more breaks and exchanges per cell. These studies clearly indicated that the treated cells accumulated in G2-phase because of their failure to progress into mitosis as a direct or indirect result of the extensive damage to the chromosomes.
Two types of chemotherapy have been compared in a randomized trial to treat non-Hodgkin malignant lymphomas. 66 patients were included in this study, but only 40 were evaluable after a histologic review of all cases. Treatment were an association of cyclophosphamide, vincristine, prednisone and doxorubicine or VM 26. Patients received only one induction chemotherapy course during 15--20 days. Results were evaluated immediately at the end of the course. Side-effects were mild. Efficacy was about the same with the two protocols: 35 patients out of 40 experienced a remission of more than 50% (among them 8 experienced a complete remission). These results are better than previous one obtained with cyclophosphamide, vincristine and prednisone only. It is concluded that this type of treatment is well tolerated, quickly efficient and useful before treating patients with radiotherapy or long-term chemotherapy.
The epipodophyllotoxin derivative VM 26 inhibits entry of mouse mastocytoma cells into mitosis in cell cultures at drug concentrations of 0.01--1 microgram/ml, the cells being arrested in G2 phase of the cell cycle. At higher concentrations, the compound exhibits spindle poison activity which manifests itself in a shortlasting rise in the number of cells arrested in metaphase of mitosis. These cells then disintegrate after a short period of time.
Single-drug chemotherapy was employed in a multicentric co-operative trial. Adriamycin was given to 18 patients, VM-26 to 30 and Bleomycin to 33. Almost all patients were suffering from a T3 or T4 bladder cancer with known metastases in almost 40% of cases. The vast majority of patients had already received previous treatment either chemotherapy, surgery of irradiation. Complete regression was obtained in 5% of cases; partial objective regression in 11.1% of patients treated with Adriamycin, 26.6% with VM-26 and 33.3% with Bleomycin. The results were uniformly better when high dosages of drug were employed. No clear-cut superiority of one drug over the others can be demonstrated.
A randomized clinical trial was designed by the European Organization for Research on Treatment of Cancer (EORTC) to compare the disease-free interval, the degree of malignancy of recurrence and the 5-year survival rate in stage I papillary carcinoma of the bladder after TUR only, and after TUR followed either by local thiotepa or by local VM 26 chemotherapy.
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Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity.