Effects of mitomycin C on the oxygenation and radiosensitivity of murine and human tumours in mice.

Abstract

Mitomycin C was one of the first chemotherapeutic agents to be shown to have preferential cytotoxicity toward hypoxic cells in vitro. Consequently, it has been used clinically with radiotherapy, and has stimulated considerable interest for analogue development. More recent studies also suggested a possible role for the drug in enhancing tumour blood flow; we therefore undertook a comprehensive examination of mitomycin C as a potential radiosensitizer in murine and human tumours growing in mice. Two dissimilar human tumour xenograft systems, SiHa and WiDr cells, were used as was the murine SCCVII line. Effects of mitomycin C treatment on the regional and microregional blood flow in these tumours was evaluated, and cell sorting based on dye perfusion techniques was used to study the cytotoxicity of mitomycin C as a single agent or in combination with radiation in the xenograft systems. Contrary to our expectations, no preferential killing of less-well oxygenated tumour cells in situ was observed, nor were any consistent effects on tumour blood flow found. The inclusion of mitomycin C with radiation did, however, produce a modest increase in cell killing in the hypoxic subpopulations of the xenograft system with the largest hypoxic fraction. Our results indicate that combined treatment with mitomycin C and radiation cannot be rationalized on the expectation of either complementary cytotoxicity of the modalities, or of drug-induced improvement in tumour oxygenation.