Abstract
In the present studies we have used the RIF-1 tumour in C3H mice to try to identify the mechanism(s) responsible for the enhancement of melphalan (L-PAM) induced tumour cell killing by the 2-nitroimidazole misonidazole (MISO). Most of this work was done with a single large dose of MISO (750 mg kg-1) given 30 min before injection of L-PAM. We found no effect of MISO on the repair of L-PAM-induced potentially lethal damage (PLD) as measured using an in vitro clonogenic survival assay. However, we identified three interrelated and competing processes which affect tumour cell killing by L-PAM subsequent to MISO injection. First, MISO reduces the clearance rate of L-PAM from the blood, an effect which enhances the cell killing by L-PAM. Second, MISO reduces the body temperature which produces a significant reduction in L-PAM cytotoxicity. Third, there is an enhancement of L-PAM cell killing by MISO over and above these two competing processes which is probably a result of the same mechanism by which cells in vitro are sensitized to L-PAM by pre-exposure to MISO under hypoxic conditions.
Highlights
Tumour cell survival studies Mice bearing RIF-I tumours were injected with MISO (750 mg kg- 1) or saline 30 min before various single doses of L-PAM
MISO alone at the dose used had no effect on survival but it did enhance the cytotoxicity of LPAM
There was some variability between experiments so that overlap in the data points was seen, the MISO + L-PAM treatment groups were always lower than the L-PAM-only groups within each experiment
Summary
The RIF-l tumour used in the present study is a non-immunogenic sarcoma in its syngeneic host (the C3H/Km mouse) and has been developed for in vivo-in vitro assay (Twentyman et al, 1980). It is routinely maintained by passage in vitro. Solid tumours were produced in 3-4 month old female C3H/Km mice by innoculating 2 x 105 cells in a volume of 0.05 ml into the base of the gastrocnemius muscle in the right rear leg. Drug treatments were given when the tumours were 300-600 mg.
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