Enhanced killing of mammalian cells by radiation combined with m-AMSA

Abstract

Summary.-m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50%O of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time.It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended. AMONG THE NEW CYTOTOXIC AGENTSthat therapists hope will extend the range of cancer chemotherapeutic drugs are the 9-anilinoacridines developed by Cain and his co-workers (Denny et al., 1978, and references therein). Reversibility of myelosuppression and limited other side effects are attractive features of m-AMSA (4'-[9 -acridinylamino] -methanesulphon -manisidide) the derivative on which attention has been focused initially.

Effectiveness of AMSA alone or in combination with radiation on murine fibrosarcoma pulmonary nodules

“…The similarity between AMSA and ADR as cytotoxic agents has been reported elsewhere [16,20,21]. In an earlier report, we described the cytotoxic effectiveness of ADR to be greatest against FSa cell populations enriched in S-phase [10].…”

Hypoxia-selective Radiosensitization of Mammalian Cells by Nitracrine, an Electron-affinic DNA Intercalator

“…Aerobic sensitization is a result of a different mechanism, since equivalent SER values were caused by pre-or postirradiation exposure to NC . This sensitizing action may be similar to that of other (non-nitro) intercalating agents (Roberts and Millar 1980, Wilson and Whitmore 1981, Elkind et al . 1964 .…”

“…aminoacridine with antitumour activity, amsacrine, has been shown to provide an apparent sensitization of both hypoxic and aerobic Chinese hamster cells (Roberts andMillar 1980, Wilson andWhitmore 1981), probably through its selective toxicity towards the most radioresistant S-phase s ubpopulation . N C might also interfere with the accumulation or repair of sublethal damage, as appears to occur with some other intercalating agents (Elkind et al .…”

A comparison of adriamycin and mAMSA in vitro: Cell lethality and SCE studies

“…The exposure to misonidazole in N2 reduces survival to 0-6; it is known that misonidazole shows cell-cycle specificity, in its cytotoxic action with cells in early S being most sensitive and late S/G2 cells most resistant (Whitmore & Gulyas, 1980;Stratford, 1980). The published data on the age responses of cells to ADM and mAMSA have yielded differing results (Kim & Kim, 1972;Barranco, 1975;Bhuyan et al, 1980;Deaven et al, 1978;Roberts & Millar, 1980). However, preliminary work with synchronized V79 cells (West, unpublished) (Au et al, 1981;Galloway & Wolff, 1979;Perry & Evans, 1975 proportion of non-differentially stained mitoses (1st divisions) appeared higher after treatment with 0 2,tM mAMSA than after the corresponding dose of ADM, suggesting that at these doses mAMSA may induce more mitotic delay than ADM.…”