Preclinical studies of porfiromycin as an adjunct to radiotherapy.

TLDR

Porfiromycin is a bioreductive alkylating agent that preferentially kills hypoxic EMT6 cells over aerobic ones. In vitro, porfiromycin’s toxicity to hypoxic EMT6 cells matched that of mitomycin C but was lower on aerobic cells and did not sensitize cells to X‑rays; however, in vivo, combining porfiromycin with radiation produced supra‑additive tumor cell killing by targeting complementary resistant subpopulations, while sparing normal marrow and causing minimal host toxicity, indicating a promising strategy for solid tumor treatment.

Abstract

The bioreductive alkylating agent porfiromycin (POR) is more toxic to EMT6 cells that are hypoxic at the time of treatment than to aerobic cells. The toxicity of POR to hypoxic EMT6 cells in vitro was similar to that of mitomycin C (MC): the aerobic toxicity of POR was considerably less than that of MC. Treatment of cells in vitro with POR before and during irradiation did not sensitize either hypoxic or aerobic cells to X rays; instead, only additive cytotoxicity was produced. In contrast, treatment of solid EMT6 tumors in vivo with POR plus radiation produced supra-additive cytotoxicity, as assessed by analyses of the complete dose-response curves for the killing of tumor cells by radiation alone or by POR alone. The supra-additivity of the combination regimens appeared to reflect the preferential killing by each agent of those tumor cells which were in an environment conferring resistance to the other agent. In contrast, combinations of POR and X rays produced only additive cytotoxicities to marrow CFU-GM. Supra-additive antineoplastic effects were obtained at doses of POR which produced little hematologic or other host toxicity. The complementary cytotoxicities of radiation and POR to cells in different microenvironments in solid tumors and the absence of a similar effect in normal tissue make optimized regimens combining radiotherapy and POR unusually promising for the treatment of solid tumors.