Kinetic Response of Cultured Chinese Hamster Cells to Treatment With 4′-[(9-Acridinyl-amino] methanesulphon-m-anisidide-HCl2

Tobey, Robert A.; Deaven, Larry L.; Oka, Melvin S.

doi:10.1093/jnci/60.5.1147

Cited by 30 publications

(9 citation statements)

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“…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].…”

Section: Comparison Of Empirical and Theoretical Surviving Fractions supporting

confidence: 74%

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

1984

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The cytotoxic effects in vivo of 4'-(9-acridinylamino) methanesulfon-m-anisidide (AMSA), radiation or both modalities in combination on murine fibrosarcoma (FSa) cells grown as pulmonary tumors were determined. Fourteen days following the i.v. injection of viable FSa cells, recipient mice developed between 100 and 150 visible pulmonary nodules. At that time, tumor-bearing animals were exposed to either single or combined modality treatments, as well as single and fractionated dose regimens. Animals were sacrificed 1 hour after the last treatment. Tumor nodules were excised, made into a single cell suspension and separated on the basis of cell size by centrifugal elutriation. Flow microfluorometry (FMF) was used to determine the cell-cycle parameters and the relative synchrony of the separated populations, as well as the percentage contamination by normal diploid cells in each of the tumor cell populations. Known numbers of viable cells from each elutriator fraction were injected into recipient mice to determine their colony-forming efficiency (CFE). Surviving fractions were determined by comparing the CFEs of treated FSa cells from each of the separated elutriator fractions with those of appropriate untreated controls. Following a single i.v. dose of AMSA (30 mg/kg), populations of cells enriched in S phase were the most sensitive. When a single dose of AMSA was combined with a single dose of radiation (100 rad), there was a marked schedule dependence with the more effective sequence, especially if a 12 hour interval was chosen between doses, being AMSA followed by irradiation. No schedule dependence was observed if both modalities were combined and administered under a fractionated protocol of four fractions of AMSA (5 mg/kg per fraction) and four fractions of radiation (300 rad per fraction). Under these conditions the greatest reduction in CFE was in cell subpopulations most enriched in S and G2 + M phase cells.

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Section: Comparison Of Empirical and Theoretical Surviving Fractions supporting

confidence: 74%

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

1984

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“…2). Tobey et al (1978) have pointed out that drug-induced tetraploid cells are normally among the first to die out in a drugtreated population.…”

Section: Discutssionmentioning

confidence: 99%

ICRF 159-induced cell-cycle perturbation in vitro: Its relationship to inhibition of colony-forming ability

Edgar¹,

Creighton²

1981

Br J Cancer

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Summary.-The effects of single doses of ICRF 159 (Razoxane) on the cell-cycle kinetics of lines of BHK 21S cells in vitro were studied by means of flow microfluorometry (FMF). A characteristic accumulation of cells in the 4n DNA region after 6 h in the presence of ICRF 159 was evident in cells which were sensitive to the cytotoxic effects of the agent, as judged by colony-forming assays. The subsequent accumulation of 8n cells as the major population within 24 h indicates that this 6 h effect is associated with the induction of tetraploidy through abnormal mitosis, rather than reflecting a G2 block of potential value in combination therapy. In ICRF 159-resistant sublines, the cell-cycle distributions were similarly affected, but only by doses of the drug high enough to reduce their surviving fraction. Somatic cell hybrids from crosses between sensitive and resistant cells demonstrated intermediate responses to ICRF 159, both in terms of cell-cycle kinetics and impairment of reproductive integrity.These data suggest a relationship between the 2 manifestations of the cellular action of ICRF 159, and also a possible predictive role for FMF in the assessment of response to this particular agent.

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“…Although the mechanism of action of the drug is uncertain, it is probable that its ability to bind to DNA by intercalation (Waring, 1976) is involved. Tobey et al (1978) have shown that mammalian cells in vitro have a similar response to m-AMSA and to Adriamycin (ADR), another intercalating agent. This has caused the 9-anilinoacridines to be placed in the category of cytotoxic intercalating agents such as ADR and actinomycin D (AMD).…”

Section: Among the New Cytotoxic Agentsmentioning

confidence: 99%

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

Roberts¹,

Millar²

1980

Br J Cancer

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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.

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Kinetic Response of Cultured Chinese Hamster Cells to Treatment With 4′-[(9-Acridinyl-amino] methanesulphon-m-anisidide-HCl2

Cited by 30 publications

References 0 publications

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

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

ICRF 159-induced cell-cycle perturbation in vitro: Its relationship to inhibition of colony-forming ability

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

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