Interactions of BMS-181174 and radiation: studies with EMT6 cells in vitro and in solid tumors.
N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C, (BMS-181174; previously designated as BMY25067) is a mitomycin C analog now in initial clinical trials. The experiments described in this report were performed to assess whether BMS-181174, like mitomycin C and porfiromycin, was selectively toxic to the hypoxic cells in solid tumors and might therefore prove valuable in combination with radiotherapy. In contrast to mitomycin C and porfiromycin, BMS-181174 was more toxic to aerobic EMT6 cells in vitro than to cells made acutely hypoxic. In vitro, BMS-181174 and radiation produced cytotoxicity compatible with either additive or slightly supra-additive cytotoxicity. In vivo, BMS-181174 was effective in killing cells in solid EMT6 tumors. The effects of regimens combining BMS-181174 and radiation in vivo were complex. Combinations of low doses of BMS-181174 plus a large dose of radiation were very effective in killing cells in solid tumors. However, the survival curve plateaued at high doses of BMS-181174, providing evidence for a subpopulation of tumor cells which were resistant to both BMS-181174 and radiation; this was hypothesized to be a hypoxic cell population.
Rockwell
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Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Kelley
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D000332:Aerobiosis / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use*; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000008:administration & dosage / Q000627:therapeutic use; D008937:Mitomycins; D009368:Neoplasm Transplantation; D011160:Porfiromycin / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D012878:Skin Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D013047:Specific Pathogen-Free Organisms; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D008937:Mitomycins; D011838:Radiation-Sensitizing Agents; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C; D011160:Porfiromycin