The cytocidal action of metronidazole in combination with other antineoplastic agents

Treatment of malignant gliomas in adults with BCNU plus metronidazole

“…Response rates as high as 60% have been obtained, with median response durations as long as nine months (1, 2). Recent in vitro and animal tumor data suggest that the nitroimidazoles may potentiate the cytotoxicity of a variety, of different chemotherapy agents, including the nitrosoureas (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). The mechanism by which cytotoxicity is augmented is unknown, although the augmentation is greatest against hypoxic cells.…”

“…While chemotherapy toxicity to normal tissues may also be increased, there appears to be a net increase in therapeutic index in many situations (6,7,9,10,13). While misonidazole has been the most extensively studied of the nitroimidazoles (3,4,(6)(7)(8)(9)(10)(11)13), multiple other ones have also been shown to potentiate chemotherapy, including metronidazole (5,6,12,14,15). In some test systems, metronidazole appears to be as effective as misonidazole (6,12,15), whereas in other systems it is somewhat less effective (6,9).…”

Chemosensitization by misonidazole in CCNU-treated spheroids and tumours

“…Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975; Hall & Roizin-Towle 1975;Moore et al, 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al, 1979;Clement et al, 1980;Rose et al, 1980, and reviewed by Siemann, 1984).Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and Siemann 1984 for reviews), including differential toxicity (Kelly et al, 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al, 1982), alterations of drug pharmacology or delivery (Urtasun et al, 1982;Workman et al, 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al, 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al, 1984).…”

“…Development of hypoxic cell radiosensitizers thus has a clear rationale; the observations that many of these sensitizers were preferentially toxic to hypoxic cells (Olive & McCalla 1975;Hall & Roizin-Towle 1975;Moore et al, 1976) suggested that they may be complementary to many conventional cancer chemotherapeutic agents, and could thus be used effectively in combination treatments. Indeed, in a number of instances an interaction between the sensitizer and the chemotherapeutic agent was observed (Kelly et al, 1979;Clement et al, 1980;Rose et al, 1980, and reviewed by .…”

“…Many factors have been implicated in the phenomenon of chemosensitization (see Brown 1982, and for reviews), including differential toxicity (Kelly et al, 1979), direct interactions between the sensitizer (or its toxic metabolites, which are generally produced under hypoxic conditions) and the chemotherapeutic agent itself (Taylor et al, 1982), alterations of drug pharmacology or delivery (Urtasun et al, 1982;Workman et al, 1983;Lee & Workman 1986), inhibition of repair processes by chemosensitizer treatment (Taylor et al, 1982;Mulcahy 1986), and alterations of cellular drug sensitivity, by, for example, the sensitizer selecting for surviving cells more vulnerable to the chemotherapeutic agent due to cell cycle status or other factors . Perhaps the most consistent observation, however, has been the apparent requirement of hypoxia both in vitro (Brown, 1982;Mulcahy, 1984), and in vivo Wheeler et al, 1984).…”