Misonidazole chemosensitization of EMT6 spheroids to melphalan

Horsman, Michael R.; Wood, Paul M.; Brown, J. Martin

doi:10.1016/0167-8140(89)90123-0

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…A similar, delayed depletion of GSH was observed in murine tumours and normal tissues following SR2508 administration i.p. (Horsmann et al, 1989). In both species the time of drug administration varied throughout the day so that a circadian variation alone is unlikely to be responsible for the observed effects.…”

Section: Discussionmentioning

confidence: 99%

“…An obvious interpretation is that SR2508 (not a known myelotoxic agent) may potentiate the toxicity of cyclophosphamide to bone marrow stem cells. This may occur as a result of GSH depletion in oxic cells as occurred in peripheral mononuclear cells; enhanced toxicity of cyclophosphamide (Grau et al, 1990) and other alkylators (Durand & Chaplin, 1987;Horsmann et al, 1989) to oxic cells is welldescribed in vivo and in spheroids. Allalunis et al have shown in addition that a proportion of normal marrow cells exist in a hypoxic environment (Allalunis et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide

LaCreta²,

Walczak³

et al. 1993

Br J Cancer

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide

LaCreta²,

Walczak³

et al. 1993

Br J Cancer

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Sensitization of Chinese hamster ovary cells to melphalan by etanidazole under intermittent hypoxia

Bump

Coleman

Cerce

et al. 1992

International Journal of Radiation Oncology*Biology*Physics

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Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo

Grau

Bentzen²,

Overgaard³

1990

Br J Cancer

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Summary The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF, mice.The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50s for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000mg kg-) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future.The ability of nitroimidazoles to enhance the tumour response of anti-cancer drugs has been shown by several investigators in different animal models (see review by Siemann, 1982) and is currently being investigated in phase II clinical trials. However, the mechanisms underlying the observed chemosensitisation in vivo is still not settled, although several suggestions have been made. These include the preferential killing of hypoxic cells by the nitroimidazole, changes in the pharmacokinetics and metabolism of the cancer chemotherapeutic drug, interference with the repair of potentially lethal damage and a manifestation of the in vitro pre-incubation effect observed under hypoxic conditions (Brown, 1982;Siemann, 1982. In vitro, hypoxia has been found to be a prerequisite for chemopotentiation to occur. No effect has been observed if cells were exposed to the sensitiser under aerobic conditions, unless extremely high doses were used (Smith et al., 1982). Some studies in vivo have also suggested that hypoxia plays a role in the development of chemosensitisation. The observation is primarily based on a relationship between the amount of sensitisation observed and the degree of tumour hypoxia Wheeler et al., 1984). However, the observed sensitisation generally exceeds what would be expected if the interaction between the sensitiser and the drug was restricted to the radiobiologically hypoxic tumour cell population (Brown & Hirst, 1982;Hinchliffe et al., 1983;Horsman et al., 1984). Thus the importance of hypoxic conditions for chemosensitisation in vivo is still unsettled.The aim of the present study was to investigate the selective effect of MISO and the alkylating agent cyclophosphamide (CTX) on aerobic and hypoxic cells in situ, using a clamped local tumour control assay ap...

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Misonidazole chemosensitization of EMT6 spheroids to melphalan

Cited by 3 publications

References 28 publications

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide

Sensitization of Chinese hamster ovary cells to melphalan by etanidazole under intermittent hypoxia

Cytotoxic effect of misonidazole and cyclophosphamide on aerobic and hypoxic cells in a C3H mammary carcinoma in vivo

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