Abstract
Transgenic female mice carrying the V-Ha-ras transgene linked to the MMTV promoter, which developed mammary carcinomas, were treated with selected cancer chemotherapy drugs. Agents were administered i.p. on a daily × 9 schedule when mice developed tumors that were 50–100 mg in size. Drugs which are clinically effective against breast cancer were quite efficacious in the transgenic model at their maximum tolerated dose. Doxorubicin produced excellent responses in tumor-bearing transgenic mice, with several mammary carcinomas undergoing tumor shrinkage. Two anthrapyrazoles, DuP 937 and DuP 941, novel anticancer drugs with phase 2 activity against breast cancer, were as effective as doxorubicin in the oncomice. Mitoxantrone, a synthetic agent with some properties similar to the anthracyclines, also had antitumor activity, but not as pronounced as obtained with doxorubicin or the anthrapyrazoles. Cisplatin, a drug with limited use in human breast cancer, only caused modest antitumor responses. A computerized data analysis method based on the area under the tumor growth curve was developed to better quantitate the data and provide statistical information. This quantitative analysis confirmed the high statistical significance of the activity of doxorubicin or the anthrapyrazoles in the ras transgenic model, and defined an excellent dose response relationship for each drug tested. Our results suggest that the ras transgenic model may be useful for identifying drugs that have efficacy for breast cancer in women.
Similar content being viewed by others
Abbreviations
- MMTV:
-
Mouse Mammary Tumor Virus
- AUC:
-
Area Under Curve
- MGR:
-
Mean Growth Rate
References
Geran RI, Greenberg NH, MacDonald MM, Shoemaker AM, Abbot BJ: Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3:1–103, 1972
Goldin A, Venditti JM, MacDonald JS, Maggio FM, Henney JE, DeVita VT: Current results of the screening program at Division of Cancer Treatment, National Cancer Institute. Eur J Cancer 17:129–142, 1981
Mattern J, Bak M, Hahn EW, Volm M: Human tumor xenografts as models for drug testing. Cancer Metas Rev 7:263–284, 1988
Grindey GB: Current status of cancer drug development: failure or limited success? Cancer Cells 2:163–171, 1990
Jackson RC, Sebot JS, Shillis JL, Leopold WR: The pyrazoloacridines: approaches to the development of a carcinoma-selective agent. Cancer Invest 8:39–47, 1990
Corbet TH, Valeriote FA, Baker LH: Is the p388 murine tumor no longer adequate as a drug discovery model? Invest New Drugs 5:3–20, 1987
Gorden JW, Ruddle FH: Gene transfer into mouse embryos; production of transgenic mice by pronuclear injection. Methods Enzymol 101:411–433, 1983
Brinster RL, Chen HY, Trumbauer ME, Yagle MK, Palmiter RD: Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci USA 82:4438–4442, 1985
Adams JM, Cory S: Transgenic models of tumor development. Science 254:1161–1167, 1991
Hanahan D. Transgenic mice as probes into complex systems. Science 246:1265–1275, 1989
Sinn E, Muller W, Pattengale P, Templer I, Wallace R, Leder P: Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice; synergistic action of oncogenesin vivo. Cell 49:465–475, 1987
Dexter DL, Diamond MA: Chemotherapy of mammary carcinomas in transgenic mice carrying the MMTV/v-Ha-ras transgene. Proc Am Assoc Cancer Res 32:382, 1991
Huang AL, Ostrowski MC, Berqrd D, Hager GL: Glucocor-ticoid regulation of the Ha-MuSV p21 gene conferred by sequences from mouse mammary tumor virus. Cell 27: 245–255, 1981
Young RC, Ozols RF, Meger CE: The anthracycline antineoplastic drugs. N-Eng J Med 305:139–153, 1981
Kolaric K, Roth A: Phase II trial ofcis-dichlorodiammine platinum (ciss-DDP) for antitumorigenic activity in previously untreated patients with metastatic breast cancer. Cancer Chemother Pharmacol 11:108–112, 1983
Hortobagyi GH: Is cisplatin useful for breast cancer? Eur J Cancer Clin Oncol 23:119–121, 1987
Cornbleet MA: Mitoxantrone for the treatment of advanced breast cancer: single agent therapy in previously untreated patients. Eur J Cancer Clin Oncol 20:1141–1146, 1984
Showalter HDH, Fry DW, Leopold WR, Lown JW, Plambeck JA, Reszka K: Design biochemical pharmacology electrochemistry and tumor biology of anti-tumor anthrapyrazoles. Anti-cancer Drug Design 1:73–85, 1986
Grahm MA, Newell DR, Butler J, Hoey B, Patterson LH: The effect of anthrapyrazole antitumor agent CI 941 on rat liver microsomes and cytochrome P-450 reductase-medicated free radical process. Biochem. Pharmacol 36:3345–3351, 1987
Talbot DC, Smith IE, Mansi JL, Judson I, Calvert AH, Ashley SE: Anthrapyrazole CI 941: a highly active new agent in the treatment of advanced breast cancer. J Clin Oncol 9:2141–2147, 1991
Allegra JC, Woodcock T, Woolf S: A randomized trial comparing mitoxantrone with doxorubicin in patients with stage IV breast cancer. Inves New Drugs 3:153–161, 1985
Henderson IC: Randomized clinical trial comparing mitoxantrone with doxorubicin in previously treated patients with metastatic breast cancer. J Clin Oncol 7:560–571, 1989
Mahon KA, Chepelinsky AB, Khillan JS, Overbeek PA, Piatigorsky J, Westphal H: Oncogenesis of the lens in transgenic mice. Science 235:1622–1628, 1987
Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54:105–115, 1988
Sandrgen EP, Quaife CJ, Paulovich AG, Palmiter RD, Brinster RL: Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci USA 88:93–97, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dexter, D.L., Diamond, M., Creveling, J. et al. Chemotherapy of mammary carcinomas arising in ras transgenic mice. Invest New Drugs 11, 161–168 (1993). https://doi.org/10.1007/BF00874150
Issue Date:
DOI: https://doi.org/10.1007/BF00874150