[Mechanism of action and resistance of antineoplastic agents].
The mechanisms of action of, and resistance to, important anticancer agents are briefly described. Their selective toxicity is considerably high, and is chiefly due to the distribution and metabolism in the body. The selective toxicity of some DNA-binding drugs may be attributed to the structural difference of DNA, nucleosome and/or chromatin between neoplastic and normal cells. Some studies of reducing side effects are summarized. In our laboratory, we are studying drug-resistance and metastasis of tumor cells. Since the mechanism of natural resistance of gastric cancer, pulmonary cancer, and other refractory cancers may be related to acquired resistance of leukemia, studies on new agents against drug-resistant tumor cells are important. In our laboratory, we have selected cell sublines of murine T-lymphoblastoma L5178Y for resistance to adriamycin (ADM), aclarubicin (ACR) or bleomycin (BLM), and have observed that the resistance is attributed to decreased influx and increased efflux of the antibiotic, resulting in lowered retention of the drug in the cells. Each resistant subline shows a characteristic cross-resistant pattern, suggesting that membrane alteration involved differs each other. We have also found that glycoprotein-synthesizing activity and alkaline phosphodiesterase activity of plasma membrane are higher in the three resistant sublines than in the parental cell line. We obtained a number of hybridomas producing antibodies to plasma membrane of an ACR-resistant subline of L5178Y cells. Among the syngeneic monoclonal antibodies, one was found by agglutination tests to react with the ACR-resistant cell line, but not significantly with the parental and ADM-, BLM-and MCR-resistant cell lines. Fluorographs of [14C] leucine-labeled ACR-resistant cells demonstrates two protein bands of 230 K and 20 K daltons, which are precipitated by the monoclonal antibody. The former seems to be specific to the ACR-resistant cells. Based on the results so far obtained, the 230 K protein may be related to the drug resistance and may be TATA (tumor-associated transplantation antigen). The results suggest that isolation of drug-resistant neoplastic cells is a novel method of finding TATA.
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000912:Antibodies, Neoplasm / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D006649:Histocompatibility Antigens / Q000032:analysis; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D006649:Histocompatibility Antigens; C029237:tumor-associated transplantation antigen; D001761:Bleomycin; D004317:Doxorubicin