Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1989 Dec;60(6):819–826. doi: 10.1038/bjc.1989.373

N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo.

R Ganapathi 1, D Grabowski 1, T W Sweatman 1, R Seshadri 1, M Israel 1
PMCID: PMC2247277  PMID: 2605093

Abstract

N-Benzyladriamycin-14-valerate (AD198) is a novel lipophilic anthracycline with greater in vivo antitumour activity than doxorubicin (DOX) in experimental model systems. Using sensitive and progressively DOX-resistant L1210 mouse leukaemia and B16-BL6 mouse melanoma lines, we have determined the cellular pharmacokinetics and cytotoxic response in vitro and in vivo of AD198. In the L1210 leukaemia model following 3 h drug exposure in vitro, the IC50 for AD198 was approximately 0.35 microgram ml-1 for the sensitive and 10-fold DOX resistant cells and 1.0 microgram ml-1 for the 40-fold DOX resistant cells. A similar pattern of cross-resistance to AD198 was also observed with the B16-BL6 melanoma, with and IC50 for AD198 with the sensitive and 10-fold DOX-resistant cells being similar, and about 2-fold higher with the 40-fold resistant cells. In the L1210 leukaemia model, cellular pharmacokinetics of AD198 revealed the following: (a) accumulation of AD198 was concentration but not time dependent, and cellular drug levels in the sensitive and resistant sublines were similar when treated with equimolar concentrations; (b) retention of AD 198 was 60% of the initial drug uptake and, in cells treated with the IC50 of AD198, cellular levels in the 40-fold DOX-resistant line were, as expected, 2-fold higher than in sensitive or 10-fold DOX-resistant cells; (c) in vitro biotransformation of AD 198 in the sensitive and resistant sublines was comparable. Studies in vivo with i.p. L1210 leukaemia (disseminating) and B16-BL6 melanoma (non-disseminating) tumour models evaluating therapeutic efficacy of DOX vs AD 198 in mice implanted with tumour i.p. on day 0 and treated i.p. on days 1-4 indicated: (a) DOX at 3 mg kg-1 administered once daily on days 1-4 resulted in a 55% ILS and 104% ILS with parent-sensitive B16-BL6 melanoma and L1210 leukaemia models respectively; however, similar doses of DOX in the resistant sublines were ineffective, with survival similar to the untreated control; (b) AD198 at 10-12.5 mg kg-1 day-1 for 4 days was extremely effective in the sensitive L1210 (189% ILS), and similar to DOX (61% ILS) in the sensitive B16-BL6; (c) AD198 (10-12.5 mg kg-1) was ineffective (survival similar to untreated control) in the 10-and 40-fold DOX-resistant L1210 leukaemia and 40-fold DOX resistant B16-BL6 melanoma, but produced a 76% ILS in the 10-fold DOX resistant B16-BL6 melanoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Full text

PDF
819

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blum R. H., Carter S. K. Adriamycin. A new anticancer drug with significant clinical activity. Ann Intern Med. 1974 Feb;80(2):249–259. doi: 10.7326/0003-4819-80-2-249. [DOI] [PubMed] [Google Scholar]
  2. Chandrasekaran B., Dimling J., Capizzi R. L. Cross-resistance of menogaril and mitoxantrone in a subline of P388 leukemia resistant to doxorubicin. Cancer Treat Rep. 1987 Feb;71(2):195–196. [PubMed] [Google Scholar]
  3. Ganapathi R., Grabowski D. Differential effect of the calmodulin inhibitor trifluoperazine in modulating cellular accumulation, retention and cytotoxicity of doxorubicin in progressively doxorubicin-resistant L1210 mouse leukemia cells. Lack of correlation between cellular doxorubicin levels and expression of resistance. Biochem Pharmacol. 1988 Jan 15;37(2):185–193. doi: 10.1016/0006-2952(88)90716-2. [DOI] [PubMed] [Google Scholar]
  4. Ganapathi R., Grabowski D. Enhancement of sensitivity to adriamycin in resistant P388 leukemia by the calmodulin inhibitor trifluoperazine. Cancer Res. 1983 Aug;43(8):3696–3699. [PubMed] [Google Scholar]
  5. Ganapathi R., Grabowski D., Rouse W., Riegler F. Differential effect of the calmodulin inhibitor trifluoperazine on cellular accumulation, retention, and cytotoxicity of anthracyclines in doxorubicin (adriamycin)-resistant P388 mouse leukemia cells. Cancer Res. 1984 Nov;44(11):5056–5061. [PubMed] [Google Scholar]
  6. Ganapathi R., Grabowski D., Schmidt H., Bell D., Melia M. Characterization in vitro and in vivo of progressively adriamycin-resistant B16-BL6 mouse melanoma cells. Cancer Res. 1987 Jul 1;47(13):3464–3468. [PubMed] [Google Scholar]
  7. Ganapathi R., Grabowski D., Schmidt H., Seshadri R., Israel M. Calmodulin inhibitor trifluoperazine selectively enhances cytotoxic effects of strong vs weak DNA binding antitumor drugs in doxorubicin-resistant P388 mouse leukemia cells. Biochem Biophys Res Commun. 1985 Sep 16;131(2):912–919. doi: 10.1016/0006-291x(85)91326-9. [DOI] [PubMed] [Google Scholar]
  8. Ganapathi R., Yen A., Grabowski D., Schmidt H., Turinic R., Valenzuela R. Role of the calmodulin inhibitor trifluoperazine on the induction and expression of cell cycle traverse perturbations and cytotoxicity of daunorubicin and doxorubicin (adriamycin) in doxorubicin-resistant P388 mouse leukaemia cells. Br J Cancer. 1986 Apr;53(4):561–566. doi: 10.1038/bjc.1986.88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gerlach J. H., Endicott J. A., Juranka P. F., Henderson G., Sarangi F., Deuchars K. L., Ling V. Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature. 1986 Dec 4;324(6096):485–489. doi: 10.1038/324485a0. [DOI] [PubMed] [Google Scholar]
  10. Gerlach J. H., Kartner N., Bell D. R., Ling V. Multidrug resistance. Cancer Surv. 1986;5(1):25–46. [PubMed] [Google Scholar]
  11. Inaba M., Kobayashi H., Sakurai Y., Johnson R. K. Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia. Cancer Res. 1979 Jun;39(6 Pt 1):2200–2203. [PubMed] [Google Scholar]
  12. Israel M., Modest E. J., Frei E., 3rd N-trifluoroacetyladriamycin-14-valerate, an analog with greater experimental antitumor activity and less toxicity than adriamycin. Cancer Res. 1975 May;35(5):1365–1368. [PubMed] [Google Scholar]
  13. Israel M., Seshadri R., Koseki Y., Sweatman T. W., Idriss J. M. Amelioration of adriamycin toxicity through modification of drug-DNA binding properties. Cancer Treat Rev. 1987 Dec;14(3-4):163–167. doi: 10.1016/0305-7372(87)90003-x. [DOI] [PubMed] [Google Scholar]
  14. Johnson R. K., Chitnis M. P., Embrey W. M., Gregory E. B. In vivo characteristics of resistance and cross-resistance of an adriamycin-resistant subline of P388 leukemia. Cancer Treat Rep. 1978 Oct;62(10):1535–1547. [PubMed] [Google Scholar]
  15. Louie K. G., Hamilton T. C., Winker M. A., Behrens B. C., Tsuruo T., Klecker R. W., Jr, McKoy W. M., Grotzinger K. R., Myers C. E., Young R. C. Adriamycin accumulation and metabolism in adriamycin-sensitive and -resistant human ovarian cancer cell lines. Biochem Pharmacol. 1986 Feb 1;35(3):467–472. doi: 10.1016/0006-2952(86)90221-2. [DOI] [PubMed] [Google Scholar]
  16. Maniar N., Krishan A., Israel M., Samy T. S. Anthracycline-induced DNA breaks and resealing in doxorubicin-resistant murine leukemic P388 cells. Biochem Pharmacol. 1988 May 1;37(9):1763–1772. doi: 10.1016/0006-2952(88)90440-6. [DOI] [PubMed] [Google Scholar]
  17. Silber R., Liu L. F., Israel M., Bodley A. L., Hsiang Y. H., Kirschenbaum S., Sweatman T. W., Seshadri R., Potmesil M. Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. NCI Monogr. 1987;(4):111–115. [PubMed] [Google Scholar]
  18. Skovsgaard T. Mechanisms of resistance to daunorubicin in Ehrlich ascites tumor cells. Cancer Res. 1978 Jun;38(6):1785–1791. [PubMed] [Google Scholar]
  19. Tewey K. M., Rowe T. C., Yang L., Halligan B. D., Liu L. F. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984 Oct 26;226(4673):466–468. doi: 10.1126/science.6093249. [DOI] [PubMed] [Google Scholar]
  20. Tsuruo T., Iida H., Tsukagoshi S., Sakurai Y. Increased accumulation of vincristine and adriamycin in drug-resistant P388 tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res. 1982 Nov;42(11):4730–4733. [PubMed] [Google Scholar]
  21. Young R. C., Ozols R. F., Myers C. E. The anthracycline antineoplastic drugs. N Engl J Med. 1981 Jul 16;305(3):139–153. doi: 10.1056/NEJM198107163050305. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES