Collateral sensitivity to methotrexate in cells resistant to adriamycin

T. S. Herman, Anne E Cress, E. W. Gerner

Research output: Contribution to journalArticle

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Abstract

Chinese hamster ovary (CHO) cells, maintained and treated in log-phase growth, are extremely sensitive to Adriamycin but are very resistant to methotrexate-induced cell killing. The survival response to Adriamycin is biphasic, with the sensitive population showing a D(o) of 0.08 μg/ml for 1 hr, while essentially no cell killing is produced by methotrexate treatments of up to 500 μg/ml for either 1 or 13 hr. Cells surviving Adriamycin treatment (5 μg/ml for 1 hr) and isolated in colony form were more resistant (Do=0.2μg/ml) to subsequent treatments with Adriamycin than were the parental population, although the survival response was still biphasic. These Adriamycin-resistant cells (CHO-R/ADR), however, had become sensitive to methotrexate, with a nearly 50% cell killing achieved by treatment with 5 μg/ml for 1 hr. Uptake studies indicate that the acquired Adriamycin resistance is not due to a decrease in Adriamycin uptake, whereas the increase in methotrexate sensitivity is, in part, due to an increased uptake and a lower efflux of methotrexate. Levels of dihydrofolate reductase activity in the Adriamycin-sensitive methotrexate-resistant CHO cells are substantially higher (35%) than levels in Adriamycin-resistant (CHO-R/ADR) cultures. Titration of CHO cells with methotrexate doses of up to 500 μg/ml (for only 1 hr) reduced the dihydrofolate reductase activity to the level found in CHO-R/ADR cells treated with doses up to 5 μg/ml for 1 hr. Survival studies confirmed that Adriamycin resitance could be conferred to the CHO cells in a dose-dependent fashion by pretreating normal cultures with methotrexate. These and other data suggest that the collateral methotrexate sensitivity in the CHO-R/ADR cells is on the basis of both decreased levels of dihydrofolate reductase and increased net uptake of methotrexate. Dihydrofolate reductase levels seem to be a measure of Adriamycin sensitivity. These results may have important implications in the use of these two drugs, either alone or in combination, in cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)1937-1942
Number of pages6
JournalCancer Research
Volume39
Issue number6 I
StatePublished - 1979

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Methotrexate
Doxorubicin
Cricetulus
Ovary
Tetrahydrofolate Dehydrogenase
Survival
Vulnerable Populations
Therapeutics
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Collateral sensitivity to methotrexate in cells resistant to adriamycin. / Herman, T. S.; Cress, Anne E; Gerner, E. W.

In: Cancer Research, Vol. 39, No. 6 I, 1979, p. 1937-1942.

Research output: Contribution to journalArticle

Herman, TS, Cress, AE & Gerner, EW 1979, 'Collateral sensitivity to methotrexate in cells resistant to adriamycin', Cancer Research, vol. 39, no. 6 I, pp. 1937-1942.
Herman, T. S. ; Cress, Anne E ; Gerner, E. W. / Collateral sensitivity to methotrexate in cells resistant to adriamycin. In: Cancer Research. 1979 ; Vol. 39, No. 6 I. pp. 1937-1942.
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title = "Collateral sensitivity to methotrexate in cells resistant to adriamycin",
abstract = "Chinese hamster ovary (CHO) cells, maintained and treated in log-phase growth, are extremely sensitive to Adriamycin but are very resistant to methotrexate-induced cell killing. The survival response to Adriamycin is biphasic, with the sensitive population showing a D(o) of 0.08 μg/ml for 1 hr, while essentially no cell killing is produced by methotrexate treatments of up to 500 μg/ml for either 1 or 13 hr. Cells surviving Adriamycin treatment (5 μg/ml for 1 hr) and isolated in colony form were more resistant (Do=0.2μg/ml) to subsequent treatments with Adriamycin than were the parental population, although the survival response was still biphasic. These Adriamycin-resistant cells (CHO-R/ADR), however, had become sensitive to methotrexate, with a nearly 50{\%} cell killing achieved by treatment with 5 μg/ml for 1 hr. Uptake studies indicate that the acquired Adriamycin resistance is not due to a decrease in Adriamycin uptake, whereas the increase in methotrexate sensitivity is, in part, due to an increased uptake and a lower efflux of methotrexate. Levels of dihydrofolate reductase activity in the Adriamycin-sensitive methotrexate-resistant CHO cells are substantially higher (35{\%}) than levels in Adriamycin-resistant (CHO-R/ADR) cultures. Titration of CHO cells with methotrexate doses of up to 500 μg/ml (for only 1 hr) reduced the dihydrofolate reductase activity to the level found in CHO-R/ADR cells treated with doses up to 5 μg/ml for 1 hr. Survival studies confirmed that Adriamycin resitance could be conferred to the CHO cells in a dose-dependent fashion by pretreating normal cultures with methotrexate. These and other data suggest that the collateral methotrexate sensitivity in the CHO-R/ADR cells is on the basis of both decreased levels of dihydrofolate reductase and increased net uptake of methotrexate. Dihydrofolate reductase levels seem to be a measure of Adriamycin sensitivity. These results may have important implications in the use of these two drugs, either alone or in combination, in cancer chemotherapy.",
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N2 - Chinese hamster ovary (CHO) cells, maintained and treated in log-phase growth, are extremely sensitive to Adriamycin but are very resistant to methotrexate-induced cell killing. The survival response to Adriamycin is biphasic, with the sensitive population showing a D(o) of 0.08 μg/ml for 1 hr, while essentially no cell killing is produced by methotrexate treatments of up to 500 μg/ml for either 1 or 13 hr. Cells surviving Adriamycin treatment (5 μg/ml for 1 hr) and isolated in colony form were more resistant (Do=0.2μg/ml) to subsequent treatments with Adriamycin than were the parental population, although the survival response was still biphasic. These Adriamycin-resistant cells (CHO-R/ADR), however, had become sensitive to methotrexate, with a nearly 50% cell killing achieved by treatment with 5 μg/ml for 1 hr. Uptake studies indicate that the acquired Adriamycin resistance is not due to a decrease in Adriamycin uptake, whereas the increase in methotrexate sensitivity is, in part, due to an increased uptake and a lower efflux of methotrexate. Levels of dihydrofolate reductase activity in the Adriamycin-sensitive methotrexate-resistant CHO cells are substantially higher (35%) than levels in Adriamycin-resistant (CHO-R/ADR) cultures. Titration of CHO cells with methotrexate doses of up to 500 μg/ml (for only 1 hr) reduced the dihydrofolate reductase activity to the level found in CHO-R/ADR cells treated with doses up to 5 μg/ml for 1 hr. Survival studies confirmed that Adriamycin resitance could be conferred to the CHO cells in a dose-dependent fashion by pretreating normal cultures with methotrexate. These and other data suggest that the collateral methotrexate sensitivity in the CHO-R/ADR cells is on the basis of both decreased levels of dihydrofolate reductase and increased net uptake of methotrexate. Dihydrofolate reductase levels seem to be a measure of Adriamycin sensitivity. These results may have important implications in the use of these two drugs, either alone or in combination, in cancer chemotherapy.

AB - Chinese hamster ovary (CHO) cells, maintained and treated in log-phase growth, are extremely sensitive to Adriamycin but are very resistant to methotrexate-induced cell killing. The survival response to Adriamycin is biphasic, with the sensitive population showing a D(o) of 0.08 μg/ml for 1 hr, while essentially no cell killing is produced by methotrexate treatments of up to 500 μg/ml for either 1 or 13 hr. Cells surviving Adriamycin treatment (5 μg/ml for 1 hr) and isolated in colony form were more resistant (Do=0.2μg/ml) to subsequent treatments with Adriamycin than were the parental population, although the survival response was still biphasic. These Adriamycin-resistant cells (CHO-R/ADR), however, had become sensitive to methotrexate, with a nearly 50% cell killing achieved by treatment with 5 μg/ml for 1 hr. Uptake studies indicate that the acquired Adriamycin resistance is not due to a decrease in Adriamycin uptake, whereas the increase in methotrexate sensitivity is, in part, due to an increased uptake and a lower efflux of methotrexate. Levels of dihydrofolate reductase activity in the Adriamycin-sensitive methotrexate-resistant CHO cells are substantially higher (35%) than levels in Adriamycin-resistant (CHO-R/ADR) cultures. Titration of CHO cells with methotrexate doses of up to 500 μg/ml (for only 1 hr) reduced the dihydrofolate reductase activity to the level found in CHO-R/ADR cells treated with doses up to 5 μg/ml for 1 hr. Survival studies confirmed that Adriamycin resitance could be conferred to the CHO cells in a dose-dependent fashion by pretreating normal cultures with methotrexate. These and other data suggest that the collateral methotrexate sensitivity in the CHO-R/ADR cells is on the basis of both decreased levels of dihydrofolate reductase and increased net uptake of methotrexate. Dihydrofolate reductase levels seem to be a measure of Adriamycin sensitivity. These results may have important implications in the use of these two drugs, either alone or in combination, in cancer chemotherapy.

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