Evaluation of the wap-ras transgenic mouse as a model system for testing anticancer drugs
L L Nielsen1, M Gurnani, R D Tyler
1Department of Tumor Biology, Schering-Plough Research, Bloomfield, New Jersey 07003.
Abstract:
Transgenic mouse models have provided many valuable insights into the molecular mechanisms of tumorigenesis; unfortunately, there is a paucity of published information on the utility of these models for evaluating potential anticancer therapeutics. Line 69 wap-ras transgenic mice have an activated, human c-Ha-ras gene on their Y chromosome. Adult males develop salivary and/or mammary adenocarcinomas. Both tumor types express high levels of human ras oncoprotein. Two new sublines, designated wap-ras/F, were created by selective breeding. Subline 69-2 wap-ras/F males developed multiple mammary tumors at puberty. Tumor onset was delayed by cyclophosphamide treatment prior to puberty. Mammary tumors from cyclophosphamide-treated mice weighed 0.57 +/- 0.09 g/mouse (SD +/- SEM; n = 8), while tumors from control mice weighed significantly more at 2.36 +/- 0.25 g/mouse (n = 8; P less than or equal to 0.001; SD +/- SEM). These results suggest that subline 69-2F mice will be valuable for testing therapeutic regimes designed to interfere with processes occurring early in tumorigenesis, before palpable tumor presentation. Tumor sensitivity to several clinically relevant cytotoxins was also tested in adult wap-ras males with palpable tumors. Both salivary and mammary tumors were sensitive to cyclophosphamide and 5-fluorouracil, but not methotrexate. This suggests that wap-ras transgenic mice will indeed be useful in the discovery of novel therapeutics against neoplasia.
Insights
Transgenic mice with activated ras genes develop tumors and are useful for testing anticancer drugs. Early treatment with cyclophosphamide delayed tumor growth in young mice, showing potential for early tumorigenesis intervention.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Transgenic mouse models are crucial for understanding tumorigenesis.
- Limited data exists on their use for evaluating anticancer therapeutics.
- The wap-ras transgenic mouse model expresses human c-Ha-ras, leading to adenocarcinoma development.
Purpose of the Study:
- To evaluate the utility of wap-ras transgenic mice for preclinical anticancer drug testing.
- To assess the efficacy of therapeutic interventions targeting early tumorigenesis.
- To determine tumor sensitivity to clinically relevant cytotoxins.
Main Methods:
- Development of two new sublines (wap-ras/F) through selective breeding.
- Administration of cyclophosphamide to pre-pubertal subline 69-2F males to assess impact on tumor onset.
- Testing the sensitivity of palpable salivary and mammary tumors in adult wap-ras males to cyclophosphamide, 5-fluorouracil, and methotrexate.
Main Results:
- Subline 69-2F males developed mammary tumors at puberty.
- Cyclophosphamide treatment significantly delayed tumor onset and reduced mammary tumor weight in subline 69-2F.
- Adult wap-ras tumors showed sensitivity to cyclophosphamide and 5-fluorouracil, but not methotrexate.
Conclusions:
- Subline 69-2F wap-ras mice are valuable for studying early tumorigenesis and testing therapies.
- These transgenic mice demonstrate utility in discovering novel anticancer therapeutics.
- The model shows promise for evaluating drugs targeting both early and established neoplastic processes.
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