The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse

Abstract

Summary Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37°C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics.

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

“…The breakdown of L-PAM in vivo is believed to be primarily by hydrolysis and alkylation (Evans et al, 1982). Furthermore, the hydrolysis of L-PAM has been shown to be temperature sensitive with slower rates being obtained at lower temperatures, both in water (Chang et al, 1978) and in plasma (Hinchliffe et al, 1983). Alternatively, these inhibitors may actually interfere with these processes or affect some other metabolic route.…”

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

“…Tumours that lack radiobiologically hypoxic cells show no chemopotentiation unless they are made artifically hypoxic between MISO injection and treatment with BCNU (Wheeler et al, 1984). However, the observed sensitisation exceeds what would be expected if the interaction between MISO and alkylating drugs is restricted to the small fraction of clonogenic and radiobiologically hypoxic tumour cells (Brown & Hirst, 1982;Hinchliffe et al, 1983;Horsman et al, 1984). So, while hypoxia appears to be necessary for the chemosensitisation to occur, significant effects can be seen in cells at oxygenation levels above what would render them radiobiologically hypoxic.…”

“…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.…”

Enhancement of the action of alkylating agents by single high, or chronic low doses of misonidazole

“…We have shown that large acute doses of MISO can significantly alter the pharmacokinetics of Cy and L-PAM (Hinchliffe et al, 1983) and this could account for the enhancing effect of large doses of MISO. The same cannot be true for chronic MISO doses, since they had no effect on drug pharmacology (Hinchliffe et al, 1983).…”

“…The same cannot be true for chronic MISO doses, since they had no effect on drug pharmacology (Hinchliffe et al, 1983). Brown (1982) has suggested two possible mechanisms for the enhancement of cytotoxic drug action by MISO.…”