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Cross resistance to esters of methotrexate in a doxorubicin-resistant subline of P388 murine leukemia

  • Original Articles
  • Methotrexate, Methotrexate Analogs, Doxorubicin, Drug Resistance, P388 Murine Leukemia
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Summary

Resistance to methotrexate was developed by continuous exposure of P388 murine leukemia cells in vitro to increasing concentrations of methotrexate up to 1×10-7 M. Once established, the resistance to methotrexate was stable. This was also found in methotrexate-resistant cells that were maintained in methotrexate-free medium for more than 4 months.

The sensitivity of the methotrexate-resistant P388 cells to doxorubicin was comparable to the sensitivity measured in the parental cell line.

Another methotrexate-resistant cell line was developed, in a similar way, from doxorubicin-resistant P388 cells. This methotrexate-resistant cell line maintained its original resistance to doxorubicin.

In methotrexate-sensitive cells, the dimethyl and dibutyl esters of methotrexate were 18.3- and 2.7-fold less active, respectively, than the free methotrexate in inhibiting cell growth.

In methotrexate-resistant cells, the inhibitory effect of the methotrexate dimethyl ester was similar to its effect on the methotrexate-sensitive cell line. The activity of the methotrexate dibutyl ester was 3.3-fold lower than its activity in the parental cell line. However, both esters of methotrexate were much more active than free methotrexate in the methotrexate-resistant cell line.

In the doxorubicin-resistant cell line, the activity of free methotrexate was comparable to its activity in the doxorubicin-sensitive parent cell line. However, this cell line was remarkably resistant to the ester analogs of methotrexate.

The clinical implications of these findings are discussed.

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References

  1. Beardsley GP, Rosowsky A (1980) Effect of methotrexate γ-monohexadecyl ester (γ-mHxMTX) on nucleoside uptake by human leukemic cells. Proc Am Assoc Cancer Res 21: 264

    Google Scholar 

  2. Bertino JR, Sawicki WL (1977) Potent inhibitory activity of trimethoxyquine (TMQ), “nonclassical” 2,4-diaminoquinazoline on mammalian DNA synthesis. Proc Am Assoc Cancer Res 18: 165

    Google Scholar 

  3. Brockman RW (1975) Mechanism of resistance: In: Sartorelli AC, Johns DC (eds) Antineoplastic and immunosuppresive agents, vol. 1. Springer, Berlin Heidelberg New York, P 352

    Google Scholar 

  4. Chabner BA (1982) Methotrexate. In: Chabner BA (ed) Pharmacologic principles of cancer treatment. Saunders, Philadelphia, p 229

    Google Scholar 

  5. Dawe CJ, Potter M (1957) Morphologic and biologic progression of a lymphoid neoplasm of the mouse in vivo and in vitro. Am J Pathol 33: 603

    Google Scholar 

  6. Diddens H, Niethammer D, Jackson RC (1983) Patterns of cross resistance to the antifolate drugs trimetrexate, metoprine, homofolate and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Cancer Res 43: 5286

    Google Scholar 

  7. Fischer GA (1962) Defective transport of amethopterin (methotrexate) as a mechanism of resistance to the antimetabolite in L5178Y leukemic cells. Biochem Pharmacol 11: 1233

    Google Scholar 

  8. Harrap KR, Hill BT, Furness ME, Hart LI (1971) Site of action of amethopterin: Intrinsic and acquired drug resistance. Ann NY Acad Sci 186: 312

    Google Scholar 

  9. Herman TS, Cress AE, Gerner EW (1979) Collateral sensitivity to methotrexate in cells resistant to adriamycin. Cancer Res 39: 1937

    Google Scholar 

  10. Hill BT, Price LA, Goldie JH (1975) Methotrexate resistance and uptake of DDMP by L5178Y cells. Eur J Cancer 11: 545

    Google Scholar 

  11. Hill BT, Price LA, Goldie JH (1976) The value of adriamycin in overcoming resistance to methotrexate in tissue culture. Eur J Cancer 12: 541

    Google Scholar 

  12. Hill BT, Dedhar S, Goldie JH (1982) Evidence that at “high” extracellular methotrexate concentrations the transport barrier is unlikely to be an important mechanism of drug resistance. Biochem Pharmacol 34: 263

    Google Scholar 

  13. Johns DG, Farquhar D, Chabner BA, Wolpert MK, Adamson RH (1973) Antineoplastic activity of lipid-soluble dialkyl esters of methotrexate. Experientia 29: 1104

    Google Scholar 

  14. Johnson RK, Ovejera AA, Goldin A (1976) Activity of anthracyclines against an adriamycin (NSC-123127)-resistant subline of P388 leukemia with special emphasis on cinerubin A (NSC-18334). Cancer Treat Rep 60: 99

    Google Scholar 

  15. Johnson RK, Chitnis MK, Embrey WM, Gregory EB (1978) In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia. Cancer Treat Rep 62: 1535

    Google Scholar 

  16. Kessel D, Hall TC, Roberts DW (1968) Modes of uptake of methotrexate by normal and leukemic human leukocytes in vitro and their relation to drug response. Cancer Res 28: 564

    Google Scholar 

  17. Kruyff B De, DeGreef WJ, VanEyk RV, Demel RA, Van Deenen LLM (1973) The effect of different fatty acid and sterol composition on the erythritol flux through the cell membrane of Acholeplasma Laidlawii. Biochim Biophys Acta 298: 479

    Google Scholar 

  18. Meelhaney RN, DeGier J, VanDer Neut-kok (1973) The effect of alterations in fatty acid composition and cholestrerol content on the nonelectrolyte permeability of Acholeplasma Laidlawii B cells and derived liposomes. Biochim Biophys Acta 298: 500

    Google Scholar 

  19. Nichol CA (1968) Studies on dihydrofolate reductase related to the drug sensitivity of microbial and neoplastic cells. Adv Enzyme Regul 6: 305

    Google Scholar 

  20. Niethammer D, Jackson RC (1975) Changes of molecular properties associated with the development of resistance against methotexate in human lymphoblastoid cells. Eur J Cancer 11: 845

    Google Scholar 

  21. Ohnoshi T, Ohnuma T, Takahashi I, Scanlon K, Kamen BA, Holland JF (1982) Establishment of methotrexate-resistant human acute lymphoblastic leukemia cells in culture and effects of folate antagonists. Cancer Res 42: 1655

    Google Scholar 

  22. Price LA, Goldie JH, Hill BT (1975) Methodichlorophen as anti-tumor drug. Br Med J II: 20

    Google Scholar 

  23. Ramu A, Glaubiger D, Magrath IT, Joshi A (1983) Plasma membrane lipid structural order in doxorubicin-sensitive and-resistant P388 cells. Cancer Res 43: 5533

    Google Scholar 

  24. Rosowsky A (1973) Methotrexate analogs. 2: A facile method of preparation of lipophilic derivatives of methotrexate and 3′, 5′-dichloromethotrexate by direct esterification. J Med Chem 16: 1190

    Google Scholar 

  25. Rosowsky A, Lazarus H, Yuan GC, Beltz WR, Mangini L, Abelson HT, Modest EJ, Frei E III (1980) Effect of methotrexate esters and other lipophilic antifolates on methotrexate-resistant human leukemic lymphoblasts. Biochem Pharmacol 29: 648

    Google Scholar 

  26. Rosowsky A, Cucchi C, Forsch R, Wright JE, Frei E III (1983) Methotrexate γ-Tert-butyl ester (γ-tBMTX): A stable lipophilic derivative with limited cross-resistance to methotrexate (MTX). Proc Am Assoc Cancer Res 24: 274

    Google Scholar 

  27. Sirotnak FM, Moccio DM, Goutas LJ, Kelleher LE, Montgomery JA (1982) Biochemical correlates of responsiveness and collateral sensitivity of some methotrexate-resistant murine tumors to the lipophilic antifolate, metoprine. Cancer Res 42: 924

    Google Scholar 

  28. Skeel RT, Sawicki WL, Cashmore AR, Bertino JR (1973) The basis for the disparate sensitivity of L1210 leukemia and Walker 256 carcinoma to a new triazine folate antagonist. Cancer Res 33: 2972

    Google Scholar 

  29. Wilkoff LJ, Dulmadge EA (1978) Resistance and cross-resistance of cultured leukemia cells to vincristine, adriamycin, adriamycin analogs and actinomycin D. J Natl Cancer Inst 61: 1521

    Google Scholar 

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Authors and Affiliations

  1. Department of Radiation and Clinical Oncology, Hadassah University Hospital, 91120, Jerusalem, Israel

    Avner Ramu

  2. Department of Organic Chemistry, Weizmann Institute for Science, Rehovot, Israel

    Mati Fridkin & Reuben Steinherz

  3. Department of Pediatrics A, Beilinson Medical Center and The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Reuben Steinherz

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  1. Avner Ramu
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  2. Mati Fridkin
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  3. Reuben Steinherz
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Ramu, A., Fridkin, M. & Steinherz, R. Cross resistance to esters of methotrexate in a doxorubicin-resistant subline of P388 murine leukemia. Cancer Chemother. Pharmacol. 15, 31–34 (1985). https://doi.org/10.1007/BF00257290

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  • DOI: https://doi.org/10.1007/BF00257290

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