Solid tumors contain deficient vascular beds and areas of severe vascular insufficiency and, as a consequence, develop regions containing hypoxic cells. These oxygen deficient malignant cells, which frequently constitute 5 to 30 percent of the total viable tumor cell population, represent a therapeutically resistant group of cells that limits the curability of many solid tumors by radiation and most chemotherapeutic agents. Thus, hypoxic neoplastic cells may be capable of proliferating and causing tumor regrowth after treatments that produce tumor regression. However, hypoxia creates an environment conducive to reductive events that results in a major exploitable difference between normal and neoplastic cells. The primary objective of this grant application is to employ the exceedingly efficacious and broad spectrum activity of the 1-(2-chloroethyl)sulfonylhydrazine family of agents to develop prodrugs of this class with preferential toxicity to hypoxic cells of solid tumors relative to their aerobic counterparts. To accomplish this the following specific aims are planned: 1. The synthesis of a prodrug with a large pH-dependent shift in redox potential such that the bioreductive activation of the drug occurs more readily under the acidic conditions found in areas of solid tumors that at the physiological pH value present in well oxygenated normal tissue and that this property is important to the preferential kill of hypoxic tumor cells. The agent will also be designed to have an appropriate balance between hydrophobicity and hydrophilicity to permit penetration of the solid tumor to reach unperfused hypoxic tumor areas in adequate cytotoxic concentrations; 2. A determination of the role of NADPH:cytochrome C (P450) reductase, NADH:cytochrome b5 reductase and DT-diaphorase in the reductive action of the prodrug, employing purified enzymes and cells overexpressing each of these catalysts to ascertain their involvement in situ under conditions of aeration and hypoxia; and 3. A determination of the importance of DNA cross-links to cell death.
| Finch, R A; Shyam, K; Penketh, P G et al. (2001) 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine (101M): a novel sulfonylhydrazine prodrug with broad-spectrum antineoplastic activity. Cancer Res 61:3033-8 |
| Penketh, P G; Shyam, K; Sartorelli, A C (2000) Comparison of DNA lesions produced by tumor-inhibitory 1,2-bis(sulfonyl)hydrazines and chloroethylnitrosoureas. Biochem Pharmacol 59:283-91 |
| Shyam, K; Penketh, P G; Shapiro, M et al. (1999) Hypoxia-selective nitrobenzyloxycarbonyl derivatives of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines. J Med Chem 42:941-6 |
| Rockwell, S (1998) Experimental radiotherapy: a brief history. Radiat Res 150:S157-69 |
