Abstract
The effect of melphalan alone or combined with various schedules of misonidazole (MISO) has been tested on a murine fibrosarcoma. The tumoricidal effect has been determined using the growth delay assay. Large single doses (500-1000 mgkg-1) of MISO enhanced the anti-tumour effect of melphalan, especially at high melphalan doses. This was accompanied by a drop in body and tumour temperature and an increase in the melphalan half-life. The MISO-induced hypothermia was prevented in one experiment by keeping the mice in an ambient temperature of 35 degrees C for 3 h. This reduced the exposure to melphalan but did not diminish the cytotoxic effect of the drug combination. Chronic administration of MISO for an 8 h period gave no enhancement of melphalan damage, whether melphalan was given half-way through or at the end of the period of dosing. It seems that a threshold tumour concentration of MISO, in excess of 70 micrograms g-1, is needed for enhancement of melphalan cytotoxicity; prolonged exposures to very low doses are ineffective.
Highlights
In this paper we report a comparison of the response of a fibrosarcoma (SA FA) to melphalan given in combination with large single doses of MISO, or small but prolonged exposures
Increasing growth delay was seen with increasing melphalan dose
One thousand mgkg-1 MISO gave -2 days delay in growth. This MISO dose enhanced the growth delay obtained with all melphalan doses, especially at the higher doses
Summary
The fibrosarcoma SA FA grown in WHT/Gy f BSVS mice has been used. This tumour arose spontaneously and was maintained by serial passage in the inbred strain of origin at the Gray Laboratory for many years. All drugs were freshly prepared on the day of the experiment. Melphalan was first dissolved in 0.5ml of acid alcohol (2% HCI in ethanol) and further diluted with 9.5 ml of sterile saline immediately before administration (final pH2). It was administered i.p. according to the body weight of each animal in a volume of 0.01 mlg -1. For the chronic exposures 0.01 ml g- of a standard MISO solution was used, to give a priming dose of 120mg kg-1, followed by top up doses of 30 mg kg 1 every detector operating at 254 nm and a Waters 730 data min for 8 h
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