Abstract
The effect has been studied of adding either misonidazole (MISO) or metronidazole (METRO) to cytotoxic drug treatment of C3H mice bearing the RIF-1 sarcoma. The nitroimidazoles were injected 30 min before the cytotoxic drugs at a dose of 2 . 5 mmol/kg. Both clonogenic-cell survival and growth delay were measured as indicators of tumour response and depression in WBC count and acute lethality were used to indicate normal-tissue response. For melphalan, neither pretreatment agent produced any change in tumor response. For cyclophosphamide, no change was produced by METRO but a minimal increase in tumour response occurred with MISO. An enhancement of cell killing by CCNU was seen with MISO pretreatment, but there was no increase in tumour growth delay. METRO, however, did not enhance tumour response by either endpoint. WBC depression by CCNU was not enhanced by MISO pretreatment, and there was no significant reduction in the acute LD50. This indicates a therapeutic advantage from the addition of MISO to CCNU in this model system. For chlorambucil, considerable enhancement of tumour response followed either MISO or METRO pretreatment (dose-modifying factors of 2 . 0 and 1 . 4 respectively). However, the modification by MISO of normal-tissue response to chlorambucil was also enhanced by about a factor of 2, with no therapeutic gain.
Highlights
Summary.-The effect has been studied of adding either misonidazole (MISO) or metronidazole (METRO) to cytotoxic drug treatment of C3H mice bearing the RIF-1 sarcoma
Using the RIF-1 sarcoma in C3H mice, we have recently found that tumour growth delay induced by cyclophosphamide is considerably enhanced by the simultaneous administration of 5 mmol/
We describe experiments using the RIF-1 sarcoma in which we have studied the enhancement of a number of cytotoxic drugs by both MISO and the less electron-affinic 5-nitroimidazole analogue, metronidazole (METRO)
Summary
Mice and tumours.-The mice used in these was used to draw up 0-02 ml of blood, studies were inbred C3H/He supplied by which was diluted in 20 ml of "Isoton". Details of the RIF-1 mouse sarcoma have idazole (METRO) were kindly supplied by been previously described (Twentyman et al, Dr Carey Smithen of Roche Products Ltd and 1980), as have the methods used for tumour- by May & Baker Ltd respectively. They were cell inoculation into the gastrocnemius muscle dissolved in Hanks' balanced salt solution of the hind limb, the subsequent measurement (HBSS) and injected i.p. in a volume of of tumour growth, and the conversion of leg 0-04 ml/g to give a dose of 2-5 mmol/kg measurements to tumour weight (Twentyman (=500 mg/kg for MISO and 428 mg/kg for et al, 1979). The resulting brei was agitated for 45 min in a solution of 1 mg/ml of neutral protease (Type IX, Sigma Chemical Co.) (Twentyman & Yuhas, 1980) in complete
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