Summary
A B16 melanoma cell line in which resistance to doxorubicin (Dx) had been induced by in vitro exposure to the drug, was found not to be cross-resistant with 4'-deoxy-4'-iodo-doxorubicin (4'-I-Dx), a new Dx derivative. Dx was 200 times less active in resistant than in sensitive cells, whereas the iodo derivative compound had the same level of activity in both cell lines. Cytotoxicity of Dx was dependent on concentration and on length of treatment, whereas that of 4'-I-Dx was correlated only with drug concentration. In an effort to explain this different behavior, intracellular retention and distribution of the two drugs was examined. Uptake and efflux of 4'-I-Dx in sensitive and resistant cells were similar, and cellular retention of the drug was 5–25 times higher than that of Dx. In addition, intracellular distribution of the iodo-derivative compound was similar in both cell lines, whereas more nuclear Dx was found in sensitive than in resistant cells. These differences may explain not only the lack of cross-resistance, but also the different cytotoxic behavior, of 4'-I-Dx.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arcamone F (1985) Properties of antitumor anthracyclines and new development in their application: Cain memorial award lecture. Cancer Res 45:5995
Bates DA, Fung H, Mackillop WJ (1985) Adriamycin uptake, intracellular binding and cytotoxicity in Chinese hamster ovary cells. Cancer Lett 28:213
Bonadonna G, Beretta G, Tancini G, Brambilla C, Bajetta C, De Palo GM, De Lena M, Fossati-Bellani F, Gasparini M, Valagussa P, Veronesi U (1975) Adriamycin studies at the Istituto Nazionale Tumori, Milan. Cancer Chemother Rep 6:231
Capranico G, Dasdia T, Zunino F (1986) Comparison of doxorubicin-induced DNA damage in doxorubicin-sensitive and-resistant P388 murine leukemia cells. Int J Cancer 37:277
Capranico G, Riva A, Tinelli S, Dasdia T, Zunino F (1987) Markedly reduced levels of anthracycline-induced DNA strand breaks in resistant P388 leukemia cells and isolated nuclei. Cancer Res 47:3752
Davis HL, Davis TE (1979) Daunorubicin and adriamycin in cancer treatment: an analysis of their roles and limitations. Cancer Treat Rep 63:809
Finkel JM, Knapp KT, Mulligan LT (1969) Fluorometric determination of serum levels and urinary excretion of daunomycin (NSC-82151) in mice and rats. Cancer Chemother Rep 53:159
Fojo A, Akiyama S, Gottesman MM, Pastan I (1985) Reduced drug accumulation in multiple drug-resistant human KB carcinoma cell lines. Cancer Res 45:3002
Goldin A, Venditti JM, McDonald JS, Muggia FM, Henney JE, De Vita VT (1981) Current results of the screening program at the division of Cancer Treatment, National Cancer Institute. Eur J Cancer 17:129
Inaba M, Kobayashi H, Sakurai Y, Johnson RK (1979) Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines P388 leukemia. Cancer Res 39:2200
Kartner N, Evernden-Porelle D, Bradley G, Ling V (1985) Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 316:820
Kaye S, Merry S (1985) Tumor cell resistance to anthracyclines. A review. Cancer Chemother Pharmacol 14:96
Merry S, Ferherston CA, Kaye SB, Freshney RI, Plumb JA (1986) Resistance of human glioma to adriamycin “in vitro”. The role of membrane transport and its circumvention with verapamil. Br J Cancer 53: 129
Peterson RH, Meyers MB, Splengler BA, Biedler JL (1983) Alteration of plasma membrane glycopeptides and gangliosides of Chinese hamster cells accompanying development of resistance to daunorubicin and vicristine. Cancer Res 43: 222
Pommier Y, Zwelling LA, Kao-shan CS, Whang-Peng J, Bradley MO (1985) Correlations between intercalator-induced DNA strand breaks and sister chromatid exchanges, mutations, and cytotoxicity in Chinese hamster cells. Cancer Res 45:3143
Roninson IB, Abelson HT, Housman DE, Howell N, Varshavsky A (1984) Amplification of specific DNA sequences correlates with multidrug resistance in Chinese hamster cells. Nature 309:626
Seeber S, Osieka R, Schmidt CG, Achterrath W, Crooke ST (1982) In vivo resistance towards anthracyclines, etopside, and cis-diamminedichloro-platinum (II). Cancer Res 42:4719
Shoemarker RH, Curt GA, Carney DN (1983) Evidence for multidrug-resistant cells in human tumor cell population. Cancer Treat Rep 67:883
Smith BJ, Kundu D (1986) Acquired resistance to daunorubicin in a patient with acute myelogenous leukemia. Br J Cancer 34:53
Supino R, Prosperi E, Formelli F, Mariani M, Parmiani G (1986) Characterization of a doxorubicin-resistant murine melanoma line: studies on cross-resistance and its circumvention. Br J Cancer 54:33
Supino R, Mariani M, Capranico G, Colombo A, Parmiani G (1988) Doxorubicin cellular pharmacokinetics and DNA breakage in a multi-drug resistant B16 melanoma cell line. Br J Cancer (in press)
Van der Bliek AM, Van der Velde-Koerts T, Ling V, Borst P (1986) Overexpression and amplification of five genes in a multidrug-resistant Chinese hamster ovary cell line. Mol Cell Biol 6:1671
Wilkoff LJ, Dulmadge EA (1978) Resistance and cross-resistance of cultured leukemia P388 cells to vincristine, adriamycin, adriamycin analogs, and actinomycin D. J Natl Cancer Inst 61:1521
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Supino, R., Mariani, M., Prosperi, E. et al. Lack of cross-resistance of a doxorubicin-resistant B16 melanoma line with 4'-deoxy-4'-iodo-doxorubicin. Cancer Chemother. Pharmacol. 21, 251–254 (1988). https://doi.org/10.1007/BF00262780
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00262780