melphalan and propargylglycine

The expression of metallothionein (MT) in certain tumor cells has been associated with resistance to anticancer drugs. In the present study, we examined the effects of inhibition of MT synthesis on resistance to anticancer drugs of human bladder tumor which were inoculated in nude mice. The results show that pretreatment of tumor-bearing mice with zinc salts increased MT content, both in normal and tumor tissues, with a marked reduction in the antitumor activity of cisplatin, Adriamycin, and melphalan. Injection of propargylglycine, an inhibitor of cystathionase, decreased MT induction by zinc in the tumor and diminished the resistance to these drugs. These results suggest a role for MT in drug resistance in tumors, and injection of propargylglycine may provide a potential means to overcome drug resistance caused by elevation of MT levels in certain tumors.

Topics: Alkynes; Animals; Cisplatin; Colonic Neoplasms; Cysteine; Doxorubicin; Drug Resistance; Female; Fibrosarcoma; Glycine; Humans; Male; Melphalan; Metallothionein; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Pargyline; Sulfates; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Zinc Compounds; Zinc Sulfate

Metallothionein (MT) shows a protective effect against toxic actions of some antitumor drugs and gamma-irradiation in animals. Preadministration of bismuth subnitrate, an MT inducing drug, significantly reduced side effects of antitumor drugs without affecting antitumor activity of the drugs. This specific effect of bismuth on the toxicity of antitumor drugs appears to be attributable to its specific induction of MT in normal tissues, but not in tumor tissue. Preinduction of MT synthesis in the lung also prevented mice from carcinogenesis caused by cisplatin and melphalan in the lung. On the other hand, zinc compound induced MT synthesis in the tumor, and significantly suppressed the antitumor activity of some antitumor drugs. Propargylglycine (PPG), an inhibitor of cystathionine pathway, significantly inhibited MT induction by zinc in the tumor inoculated in mice, and, consequently, PPG could diminish cisplatin resistance acquired by an increase in the tumor MT levels.

Topics: Alkynes; Animals; Antineoplastic Agents; Bismuth; Cisplatin; Drug Resistance; Female; Glycine; Lung Neoplasms; Melphalan; Metallothionein; Mice; Neoplasms, Experimental; Pargyline