Effects of antineoplastic agents and hyperthermia on cytotoxicity toward chronically hypoxic glioma cells

Abstract

The effects of hyperthermia and antineoplastic agents on the cytotoxicity to normally oxygenated and chronically hypoxic glioma cells were investigated in vitro. Exposure to temperatures above 43.0°c was less cytotoxic to hypoxic cells which predominantly accumulated in the G₀/G₁ phase fraction. On the other hand, mitomycin C (MMC) and adriamycin (ADM) were preferentially cytotoxic to hypoxic cells not only at 37°c but also at elevated temperatures (42°c and 43°c). These two agents showed marked synergistic effects with hyperthermia under both oxygenated and hypoxic conditions. In contrast, bleomycin (BLM), cis-diamminedichloroplatinum(II) (CDDP), and vincristine (VCR) were preferentially cytotoxic to oxygenated cells at both 37°c and elevated temperatures. CDDP showed cytotoxic synergism with hyperthermia that appeared to be oxygen-dependent. A nitrosourea derivative, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), showed no major preferential toxicity under either oxygenated or hypoxic conditions. This study suggests that hyperthermia in combination with MMC or ADM would have a greater cytotoxic effect on hypoxic cell subpopulations of malignant gliomas.

Key Words:

• Malignant glioma in vitro
• hyperthermia
• chemotherapy
• hypoxic cell
• cell cycle