Preferential kill of hypoxic EMT6 mammary tumor cells by the bioreductive alkylating agent porfiromycin.
Hypoxic cells in solid tumors represent a therapeutically resistant population that limits the curability of many solid tumors by irradiation and by most chemotherapeutic agents. The oxygen deficit, however, creates an environment conducive to reductive processes; this results in a major exploitable difference between normal and neoplastic tissues. The mitomycin antibiotics can be reductively activated by a number of oxidoreductases, in a process required for the production of their therapeutic effects. Preferential activation of these drugs under hypoxia and greater toxicity to oxygen-deficient cells than to their oxygenated counterparts are obtained in most instances. The demonstration that mitomycin C and porfiromycin, used to kill the hypoxic fraction, in combination with irradiation, to eradicate the oxygenated portion of the tumor, produced enhanced cytodestructive effects on solid tumors in animals has led to the clinical evaluation of the mitomycins in combination with radiation therapy in patients with head and neck cancer. The findings from these clinical trials have demonstrated the value of directing a concerted therapeutic attack on the hypoxic fraction of solid tumors as an approach toward enhancing the curability of localized neoplasms by irradiation.
Sartorelli
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AC
Department of Pharmacology, Yale Cancer Center, Yale, University School of Medicine, New Haven, CT 06520, USA.
Belcourt
M F
MF
Hodnick
W F
WF
Keyes
S R
SR
Pritsos
C A
CA
Rockwell
S
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin / Q000493:pharmacokinetics / Q000494:pharmacology; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase; D010088:Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D011160:Porfiromycin / Q000493:pharmacokinetics / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D005609:Free Radicals; D017665:Hydroxyl Radical; D016685:Mitomycin; D010088:Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase; D011160:Porfiromycin