Selection of suitable combinations of antitumor drugs for treatment of malignant brain tumors: Mutagenic responses of antitumor drugs

Research Project

Project/Area Number	61480307
Research Category	Grant-in-Aid for General Scientific Research (B)
Allocation Type	Single-year Grants
Research Field	Cerebral neurosurgery
Research Institution	Toyama Medical and Pharmaceutical University
Principal Investigator	PROF. TAKAKU Akira Department of Neurosurgery,School of Medicine,Toyama Medical and Pharmaceutical, 医学部, 教授 (70004984)
Co-Investigator(Kenkyū-buntansha)	ASSISTANT prof. OKA Nobu Department of Neurosurgery,School of Medicine,Toyama Medical and Pharmaceutical, 附属病院, 講師 (10135006) 堀江幸男富山医科薬科大学, 附属病院, 助手 (20135015)
Project Period (FY)	1986 – 1988
Project Status	Completed (Fiscal Year 1988)
Budget Amount *help	¥4,700,000 (Direct Cost: ¥4,700,000) Fiscal Year 1988: ¥1,000,000 (Direct Cost: ¥1,000,000) Fiscal Year 1987: ¥1,000,000 (Direct Cost: ¥1,000,000) Fiscal Year 1986: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywords	ACNU / Chemotherapy / Drug resistance / Mutagenesis / 脳腫 / 突然変異 / 水溶性ニトロ素系抗癌剤 / 脳腫瘍 / 悪性脳腫瘍 / 抗癌剤 / 突然変異原性
Research Abstract	The antitumor compound ACNU is widely used for treatment of malignant brain tumors. We have investigated the mechanism of acquisition of ACNU resistance at the cellular level by isolating ACNU-resistant mutants from V79 Chinese hamster cells and C6 rat glioma cells after treatment of the cells with ACNU or other alkylating agents. In V79 Chinese hamster cells, ACNU at 1 to 4 ug/ml caused dose-dependent induction of drug-resistant mutants to ACNU(10 ug/ml), 8-azaguanine(20 ug/ml), adriamycin(270 ng/ml),cisplation(1 ug/ml), mitomycin C(110 ng/ml) and demecolcin (21 ng/ml),but not to ouabain(1 mM). Values for the mean lethal dose of ACNU-resistant mutants were 2.4 to 17.2 times those of the parent V79 cells. The ACNU-resistant phenotype was stable during an observation period of 13 weeks. The C6 rat glioma cells also showed a significant mutagenic response to ACNU, producing ACNU- and 5-fluorouracil-resistant mutants. The present results have the important therapeutic and mechanistic implication that ACNU is a potent mutagen and induces mutants that are resistant to ACNU and to other drugs. By addition of Ca2+- antagonist verapamil HCI to selection medium, mutants resistant to mitomycin C and adriamycin did not appear.