Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors.
The expression of several early-response genes and genes associated with malignant disease was assessed in the EMT-6/parent tumor and the EMT-6/CTX and EMT-6/CDDP in vivo resistant tumor lines growing as tumors or as monolayers in culture. In the absence of treatment the levels of mRNA for the genes c-jun, c-fos, c-myc, Ha-ras and p53 were increased in the EMT-6/CTX and EMT-6/CDDP as compared with the EMT-6/parent tumor, whereas the expression of erb-2 was similar in all three tumors. Although the cells from each of the three tumors show increased expression of early response genes after exposure to cisplatin (CDDP; 100 microM, 2 h) or 4-Hydroxyperoxycyclophosphamide (4-HC; 100 microM, 2 h) in culture, in mRNA extracted from tumor tissue these changes are absent or very small. Both C-jun and erb-2 were detectable in liver. There was increased expression of both of these genes in the livers of tumor-bearing animals as compared with non-tumor-bearing animals. The highest expression of both c-jun and erb-2 occurred in the livers of animals bearing the EMT-6/CDDP tumor. Treatment of the animals with CDDP or cyclophosphamide, in general, resulted in increased expression of both genes at 6 h post treatment. The increased expression of these genes may impart metabolic changes in the tumors and/or hosts that contribute to the resistance of these tumors to specific antitumor alkylating agents.
Dana-Farber Cancer Institute, Joint Center for Radiation Therapy, Boston, MA 02115.
D
D
Chatterjee
C J
CJ
Liu
D
D
Northey
B A
BA
Teicher
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D015152:Blotting, Northern; D002945:Cisplatin / Q000494:pharmacology; D015342:DNA Probes; D018432:Drug Resistance, Multiple / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D018734:Genes, erbB-2 / Q000235:genetics; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D007091:Image Processing, Computer-Assisted; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D015342:DNA Probes; D012333:RNA, Messenger; D002945:Cisplatin