Abstract
The survival of bone-marrow granulocyte-macrophage colony-forming units (CFU-GM), an alkylating-agent-sensitive normal tissue, was assessed in mice bearing the EMT-6 parental tumor or the in vivo resistant EMT-6/CDDP, EMT-6/CTX, EMT-6/Thio, and EMT-6/Carbo tumors. The survival pattern of the bone-marrow CFU-GM recapitulated the survival of the tumor cells, mimicking the development of resistance and reversion to sensitivity upon removal of the selection pressure for each of the four alkylating agents. When the EMT-6 parental tumor was implanted in the opposite hind limb of animals bearing the EMT-6/CDDP or EMT-6/CTX tumor, the survival of the parental tumor cells after treatment of the animals with the appropriate antitumor alkylating agent was enhanced. The EMT-6/CDDP tumor was cross-resistant to CTX and high-dose L-PAM, whereas the EMT-6/CTX tumor was somewhat resistant to CDDP and markedly sensitive to VP-16. In each case, the survival pattern of the bone-marrow CFU-GM reflected the survival of the tumor cells. These results indicate that the presence of an alkylating-agent-resistant tumor in an animal can affect the drug response of tissues distal to that tumor.
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Abbreviations
- CDDP:
-
cis-diamminedichloroplatinum(II)
- CTX:
-
cyclophosphamide
- L-PAM:
-
melphalan (L-phenylalanine mustard)
- BCNU:
-
1,3-bis(2-chloroethyl)-1-nitrosourea
- mito C:
-
mitomycin C
- VIN:
-
vincristine
- Adria:
-
doxorubicin (Adriamycin)
- VP-16:
-
etoposide (VP-16-213)
- thiotepa:
-
N,N′,N″-triethylenethiophosphoramide
References
Beck WT, Mandel G, Fabro S (1975) Physiological disposition of pentobarbital in tumor-bearing mice. Cancer Res 35:1333–1340
Beck WT, Dedmon ML, Ouellette MA (1982) Biochemical basis for impaired drug metabolism in tumor-bearing rats. Biochem Pharmacol 31:1535–1543
Fidler IJ (1990) Host and tumor factors in cancer metastasis. Eur J Clin Invest 20:481–486
Fidler IJ, Balch CM (1987) The biology of cancer metastasis and implications for therapy. Curr Probl Surg 24:131–209
Goustin AS, Leof EB, Shipley GD, Moses HL (1986) Growth factors and cancer. Cancer Res 46:1015–1029
Heppner G (1984) Tumor heterogeneity. Cancer Res 44:2259–2265
Kato R, Takanaka A, Oshima T (1968) Drug metabolism in tumor-bearing rats: II. In vivo metabolisms and effects of drugs in tumor-bearing rats. Jpn J Pharmacol 18:245–254
Lilley ER, Elion GB, Dewhirst MW, Schold SC Jr, Blum MR, Savina PM, Laskowitz DT, Bigner DD, Friedman HS (1991) Therapeutic analysis of the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR. Cancer Res 51:3906–3909
Miller BE, Miller FR, Heppner GH (1981) Interactions between tumor subpopulations affecting their sensitivity to the antineoplastic agents cyclophosphamide and methotrexate. Cancer Res 41: 4378–4381
Rosenberg MC, Colvin OM, Griffith OW, Bigner SH, Elion GB, Horton JK, Lilley E, Bigner DD, Friedman HS (1989) Establishment of a melphalan-resistant rhabdomyo-sarcoma xenograft with cross-resistance to vincristine and enhanced sensitivity following buthionine sulfoximine-mediated glutathione depletion. Cancer Res 49:6917–6922
Rosso R, Donelli MG, Franchi G, Garattini S (1971) Impairment of drug metabolism in tumor-bearing animals. Eur J Cancer 7:565–577
Teicher BA (ed) (1993) Mechanisms of resistance in oncology. Marcel Dekker, New York
Teicher BA, Frei E III (1988) Development of alkylating agent resistant human tumor cell lines. Cancer Chemother Pharmacol 21: 292–298
Teicher BA, Cucchi CA, Lee JB, Flatow JL, Rosowsky A, Frei E III (1986) Alkylating agents: in vitro studies of cross-resistance patterns. Cancer Res 46:4379–4383
Teicher BA, Holden SA, Kelley MJ, Shea TC, Cucchi CA, Rosowsky A, Henner WD, Frei E III (1987) Characterization of a human squamous carcinoma cell line resistant tocis-diamminedichloroplatinum(II). Cancer Res 47:388–393
Teicher BA, Holden SA, Jacobs JL (1987) Approaches to defining the mechanism of Fluosol-DA 20%/carbogen enhancement of melphalan antitumor activity. Cancer Res 47:513–518
Teicher BA, Holden SA, Cucchi CA, Cathcart KNS, Korbut TT, Flatow JL, Frei E III (1988) Combination ofN,N′,N″-triethylenethiophosphoramide and cyclophosphamide in vitro and in vivo. Cancer Res 48:94–100
Teicher BA, Herman TS, Holden SA, Wang Y, Pfeffer MR, Crawford JM, Frei E III (1990) Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247:1457–1461
Teicher BA, Holden SA, Herman TS, Alvarez Setomayor E, Khandekar V, Rosbe KW, Brann TW, Korbut TT (1991) Characteristics of five human tumor cell lines and sublines resistant tocis-diamminedichloroplatinum(II). Int J Cancer 47:252–260
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This work was supported by NIH grants P01-CA38493 and R01-CA47379, by a grant from the Mather's Foundation, and by a grant from Bristol-Myers-Squibb, Inc. (Wallingford, Conn.).
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Teicher, B.A., Chatterjee, D., Liu, JT. et al. Protection of bone-marrow granulocyte-macrophage colony-forming units in mice bearing in vivo alkylating-agent-resistant EMT-6 tumors. Cancer Chemother. Pharmacol. 32, 315–319 (1993). https://doi.org/10.1007/BF00686178
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DOI: https://doi.org/10.1007/BF00686178