melphalan and zinc-chloride

The effect of pretreatment with metallothionein (MT) inducers (bismuth nitrate or zinc chloride) on clastogenicity of anticancer drugs was investigated. Bismuth nitrate (50 mumol/kg) or zinc chloride (400 mumol/kg) was administered s.c. to mice once a day for two days prior to treatment with 3.3 mumol/kg of cis-diamminedichloroplatinum(II) (cis-DDP), 3.4 mumol/kg of adriamycin (ADR), 72 mumol/kg of cyclophosphamide (CPA) or 0.41 mumol/kg of L-phenylalanine mustard (L-PAM). The frequency of occurrence of erythrocytes with micronuclei in bone marrow was increased by each anticancer drug at 24 h after treatment. Micronucleus formation was significantly prevented by pretreatment with either bismuth nitrate or zinc chloride. MT concentration in bone marrow cells of mice at the time of treatment with anticancer drugs increased to 2- and 3.5-fold by pretreatment with bismuth nitrate and zinc chloride, respectively. These results indicate that MT induction in bone marrow cells effectively prevents micronucleus induction of anticancer drugs.

Topics: Animals; Antineoplastic Agents; Bismuth; Bone Marrow; Chlorides; Cisplatin; Cyclophosphamide; Doxorubicin; Male; Melphalan; Metallothionein; Mice; Mice, Inbred ICR; Micronucleus Tests; Mutagens; Nitrates; Zinc Compounds

We examined the efficacy of metallothionein induction in the prevention of the carcinogenic action of cis-platinum and melphalan administered repeatedly to mice over a relatively long period. The increased pulmonary metallothionein induced by bismuth or zinc compounds during the period of chemotherapy with cis-platinum or melphalan protected the mice from carcinogenesis of these drugs in the lung. These results suggested the efficacy of metallothionein inducers in suppression of carcinogenicity considered as a secondary effect of anticancer agents in cancer chemotherapy.

Topics: Animals; Anticarcinogenic Agents; Bismuth; Carcinogens; Chlorides; Cisplatin; Female; Lung; Lung Neoplasms; Melphalan; Metallothionein; Mice; Mice, Inbred A; Nitrates; Zinc Compounds

A number of toxic chemical and physical agents elicit the induction of a series of protein species, some of which react with the agents and render them nontoxic. A few of the induced species (such as metallothionein) are rich in thiol groups that might be expected to react with alkylating agents and render them nontoxic. If a safe means could be found for selectively enhancing the synthesis of alkylating-agent-reactive species in normal but not tumor cells, such a procedure would have ramifications in the area of cancer chemotherapy. In this report, we have utilized a variety of trace elements (Zn, Se, Cu, As) as inducers of synthesis of protective species in line CHO Chinese hamster cells and in a number of derived variants to determine whether this type of approach can be utilized to increase resistance to alkylating-agent toxicity. Our results indicate that Zn, Se and Cu elicit a protective response (increased survival, monitored by colony-forming ability) against the toxic effects of iodoacetate or melphalan, and, at least in the case of zinc, at levels that are physiologically reasonable. Arsenite appears to be a marginally effective inducer in the CHO cell and an ineffective inducer in the Cdr20F4 variant cell. The increased survival is not attributable to metallothionein inducibility, decreased availability of the alkylating agent in the medium, or decreased uptake of the drug into the trace-element-pretreated cells. The protective responses induced by zinc or selenite alone are additive in cells receiving both trace elements prior to exposure to alkylating agent, which suggests that different domains of response are elicited by the two metals. In view of reported differences in inducibility of protective proteins between normal and tumor cells, a possibility is raised for a novel approach to alkylating-agent chemotherapy that is somewhat analogous to the protocol utilized in high-dose methotrexate therapy.

Topics: Animals; Biotransformation; Cell Line; Cell Nucleus; Cell Survival; Chlorides; Cricetinae; Cricetulus; Cytoplasm; Drug Resistance; Electrophoresis, Polyacrylamide Gel; Female; Iodoacetates; Melphalan; Metalloproteins; Metallothionein; Ovary; Trace Elements; Zinc; Zinc Compounds

Suspension cultures of Chinese hamster ovary cells and three derived cadmium-resistant variants were exposed to 100 microM ZnCl2 prior to treatment with the alkylating agent, melphalan, and cytotoxicity was then determined by measuring colony-forming ability. A 10-fold or greater enhancement in survival of all zinc-pretreated cultures subsequently exposed to melphalan was observed which was unrelated to metallothionein induction capacity. Although the maximum achievable protection afforded by zinc occurred in cultures receiving 100 microM ZnCl2, concentrations of zinc only slightly in excess of levels found in human serum were shown to provide a 4.5-fold enhancement of protection, indicating that the phenomenon can also be induced at physiologically reasonable levels. These results suggest the existence of a novel zinc-inducible mechanism which protects cells against the toxic effects of alkylating agents.

Topics: Animals; Cadmium; Cell Division; Cell Line; Cell Survival; Chlorides; Cricetinae; Cricetulus; Drug Resistance; Female; Kinetics; Melphalan; Ovary; Zinc; Zinc Compounds