Misonidazole enhancement of the action of BCNU and melphalan against human melanoma xenografts

Clutterbuck, R. D.; Millar, J. L.; McElwain, T. J.

doi:10.1097/00000421-198205010-00014

Cited by 8 publications

(11 citation statements)

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“…Pharmacokinetic alterations could result in more effective delivery of MEL, producing a higher initial concentration of such DNA/MEL species discussed above. In support of this mechanism, MISO has been reported to increase both the serum retention time and peak serum level of MEL in mice (Clutterbuck et al, 1982 Preincubation with MISO did not enhance the cross-linking activity of cis-DDP (Table II). Although MISO has been found to enhance cis-DDP cytotoxicity in vitro (Stratford et al, 1980;Roizin-Towle & Hall, 1981), there is no apparent in vivo sensitization (Rose et al, 1980;Clement et al, 1980;Stephens et al, 1981).…”

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confidence: 80%

“…These include: alterations in pharmacokinetics and metabolism (Stephens et al, 1981;Tannock, 1980;Clutterbuck et al, 1982), selective toxicity towards hypoxic or non-cycling cells (Sutherland, 1974), the generation and fixation of free-radical intermediates (Clement et al, 1980), inhibition of the repair of potentially lethal damage (PLD) (Law et al, 1981;Martin et al, 1981;Siemann & Mulcahy, 1982), or reduced levels of intracellular sulphydryl-containing compounds such as glutathione (GSH) (Taylor et al, 1982a;Roizin-Towle et al, 1982) which are involved in detoxification of electrophilic drugs such as MEL and are also free-radical scavengers. Although hypoxia is a prerequisite for in vitro sensitization (Stratford et al, 1980;Roizin-Towle & Hall, 1981), its exact significance in terms of normal tissue versus tumour toxicity in vivo is unclear (Tannock, 1980;Law et al, 1981).…”

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confidence: 99%

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Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Murray¹,

Meyn²

1983

Br J Cancer

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confidence: 80%

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confidence: 99%

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Murray¹,

Meyn²

1983

Br J Cancer

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“…In Figure 3b, 1 h cross-linking enhancement factors (data from (Millar, 1982;Siemann, 1982), and may be an especially important mechanism in the case of the drugs CCNU (Lee & Workman, 1983) and melphalan (Clutterbuck et al, 1982;Hinchliffe et al, 1983). Brown & Hirst (1982) showed that a protocol involving multiple low doses of MISO, designed to mimic human serum levels of the drug, still sensitized the RIFI sarcoma to both melphalan and cyclophosphamide, with no associated increase in normal tissue toxicity as measured by white blood cell counts, bone marrow colony-forming units, or testicular damage.…”

Section: Alkaline Elutionmentioning

confidence: 99%

Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo

Murray¹,

Meyn²

1984

Br J Cancer

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Summary In the present study we have used the alkaline elution technique to study the effect of misonidazole (MISO) on the initial amount of DNA cross-linking in various normal and neoplastic tissues of C3H mice treated with nitrogen mustard (HN2) in vivo. Tissue samples for analysis of the cross-links were prepared 1 h after injection with HN2 to minimize the effect of subsequent repair processes on the yield of lesions. For mice receiving HN2 alone, the greatest level of cross-linking was found in spleen and jejunum, with the liver showing the lowest level. In animals that had been pretreated with MISO (1 mg g -1, i.p.) for 0.5 h prior to injection with HN2, the amount of cross-linking in the spleen and jejunum was not affected by MISO; however, in all other tissues that were examined, cross-linking was enhanced by MISO to a varying extent depending on the specific tissue. The greatest enhancement was observed in the liver ( x 6) and kidney (x 3.1), both of these tissues showing a greater enhancement than either of the two fibrosarcomas. The potentiation of HN2 cross-linking in a particular tissue correlated well with two cellular processes that are known to be nitroreduction-dependent in vitro, namely, the degree of MISO-induced GSH depletion and the binding of MISO to cellular macromolecules. Thus, the potentiation of cross-linking in normal tissues such as liver and kidney, and by inference in tumours, may be intimately related to the generation and/or accumulation of nitro-reduced MISO metabolites in those tissues.The potentiation of many antitumour drugs by the hypoxic cell radiosensitizer misonidazole (MISO) is now well documented (McNally, 1982;Millar, 1982;Siemann, 1982Siemann, , 1984. However, the mechanisms of chemosensitization, and in particular the role of hypoxia, have not been completely elucidated. Hypoxia during the MISO pretreatment stage has been found to be essential for the in vitro potentiation of all chemotherapy drugs studied to date, including the enhanced cytotoxicity of the bifunctional alkylating agent nitrogen mustard (HN2) to V79 cells (Stratford et al., 1980) and EMT6 tumour spheroids (Twentyman, 1982a(Twentyman, , 1982b. A requirement of hypoxia for MISO enhancement in vivo may explain why tumours generally seem to be sensitized to a greater extent than most normal tissues, although the exact situation regarding the involvement of hypoxia in vivo is unclear. However, Wheeler et al. (1984) recently showed that, at least for the drug BCNU, hypoxia induced by clamping of the leg was clearly critical for sensitization by MISO of a subcutaneous rat 9L tumour.We recently reported (Murray & Meyn, 1984) that pretreatment of mice with MISO enhanced the in vivo DNA cross-linking activity of HN2 in a murine fibrosarcoma, a tumour that contains a substantial fraction of hypoxic cells (Stone & Milas, 1978;Grdina et al., 1976

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“…misonidazole (MISO) plus melphalan (Coleman et al, 1983), benznidazole plus CCNU (Roberts et al, 1984) and MISO plus CCNU (Siemann, personal communication). Although the mechanism of nitroimidazole chemosensitization is still uncertain, it has become increasingly clear that changes in the pharmacokinetics of the cytotoxic agents by the sensitizers can play an important role (Tannock, 1980;Clutterbuck et al, 1982;Hinchliffe et al, 1983;Workman et al, 1983;Lee & Workman, 1983). The most detailed studies in our laboratory have been carried out with the combination of MISO and CCNU in mice.…”

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Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU

Lee¹,

Workman²

1985

Br J Cancer

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Summary Because the nitrosourea CCNU is given exclusively by the oral route in man, we have carried out studies in mice on the antitumour activity, acute toxicity and pharmacokinetics of oral CCNU, either alone or in combination with the chemosensitizer misonidazole. In both plasma and KHT tumour the peak concentration and "early" AUC for total nitrosoureas were about 1.4-1.5 fold greater for the oral compared to the i.p. route. These differences were reflected in the roughly twofold greater antitumour activity for the oral route. In contrast, acute toxicity tests showed that oral CCNU was 1.45 times less toxic to normal tissue, although the dose-limiting organ may be different for the two routes. Misonidazole reduced the antitumour activity of oral CCNU by dose modifying factors (DMF) of 0.58-0.71. Similarly, the acute toxicity was also diminished by a DMF of 0.74. Misonidazole has a complex effect on oral CCNU pharmacokinetics. The plasma and tumour total nitrosourea peak concentrations were reduced by 1.5 and 1.7 fold respectively. Misonidazole also reduced the "early" nitrosourea AUC, with the extent of the reduction depending on the minimum effective concentration (MEC) chosen. For example, the plasma nitrosourea AUC was reduced by factors of 1.05 and 9.6 for MEC values of 1 and 2pgml-1 respectively. We propose these pharmacokinetic changes to be the underlying mechanism for the reduction of oral CCNU cytotoxicity by misonidazole.Clinical trials of such combinations should be accompanied by detailed pharmacokinetic evaluation.

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Misonidazole enhancement of the action of BCNU and melphalan against human melanoma xenografts

Cited by 8 publications

References 0 publications

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Effect of misonidazole pretreatment on nitrogen mustard-induced DNA cross-linking in mouse tissues in vivo

Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU

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