Hypoxic cell specific chemotherapeutic agents

Abstract

Cellular subpopulations of solid tumors can be divided into compartments based upon their degree of oxygenation and their rate of proliferation. Based upon these considerations, combinations of drugs and other therapeutic modalities can be devised with the potential to eradicate the physiologically heterogeneous populations of tumor stem cells present in solid neoplasms. Selection of combinations of drugs or other treatment modalities based upon these concepts makes the inclusion of an agent or agents with the capacity to eliminate hypoxic stem cells mandatory to achieve cure. The bioreductive alkylating agent, mitomycin C, would appear to be the most efficacious agent presently available for this purpose, and it is proposed that this antibiotic be considered as an addition to therapeutic regimens designed for the treatment of solid tumors. To employ this agent in a manner that minimizes its toxicity to normal cellular elements, it is necessary to consider that the mechanism by which mitomycin C exerts its cytotoxicity to oxygenated cells is different from that by which it kills hypoxic cells. Mitomycin C can undergo 1-electron reduction in the presence of oxygen (46, 47). Subsequent reoxidation of the antibiotic by molecular oxygen can lead to the generation of superoxide radical and other toxic oxygen-containing species, such as hydrogen peroxide and hydroxyl radical. Such cyclic reduction and oxidation of mitomycin C by oxygenated cells may result in the generation of levels of toxic oxygen species that surpass the detoxification capacity of cellular scavenging systems, and thereby may be responsible for the toxicity of this antibiotic to aerated cells in tumors and normal tissues, whereas the cytotoxicity of mitomycin C to hypoxic cells may involve the 2-electron reduction and generation of the reactive quinone methide species shown in Figure 3. These considerations dictate that to maximize the differential toxicity of an agent such as mitomycin C to hypoxic cells requires that it be given in relatively low doses, perhaps by constant infusion to maximize its potential for diffusion into neoplastic masses to reach hypoxic stem cells.