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Nude mouse models as predictors of chemotherapy in man: thymidine and pyrimidines
Abstract:
The National Cancer Institute cancer treatment screening program has been reorganized incorporating, as an important feature, a panel of human tumors growing as xenografts in congenitally athymic mice. The new screening program is a prospective experiment in the search for new and more effective agents for the treatment of clinical neoplasia. The new program is described and questions that are being asked prospectively are presented. Data are summarized on the activity against human tumor xenografts for a number of clinically established antitumor drugs and examples are presented in which there is interest in compounds for the clinic on the basis of activity in the new screen. Studies are outlined in which high dose thymidine inhibited the growth of human melanoma and teratocarcinoma transplanted in athymic mice. Studies are discussed employing murine tumors in which marked augmentation of the in vivo antitumor activity of 5-fluorouracil was obtained by combination therapy with the pyrimidine nucleosides thymidine, uridine and cytidine. The desirability of investigating combination chemotherapy with pyrimidine nucleosides and 5-fluorouracil and other pyrimidine antagonists in the treatment of human tumor xenografts is stressed. There is a broad range of investigations that can be conducted in nude mouse models and it is important to conduct such programs in relation to the clinic.
Insights
The National Cancer Institute
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- The National Cancer Institute reorganized its cancer treatment screening program.
- A key feature is the use of human tumor xenografts in athymic mice.
- This program aims to discover novel and effective anti-cancer agents.
Purpose of the Study:
- To describe the new screening program and its prospective research questions.
- To summarize existing data on clinically established antitumor drugs against human tumor xenografts.
- To highlight promising compounds for clinical investigation based on xenograft model activity.
Main Methods:
- Utilizing a panel of human tumors grown as xenografts in congenitally athymic mice.
- Testing clinically established antitumor drugs for activity against these xenografts.
- Investigating combination chemotherapy strategies, including high-dose thymidine and 5-fluorouracil with pyrimidine nucleosides.
Main Results:
- High-dose thymidine demonstrated inhibition of human melanoma and teratocarcinoma growth in athymic mice.
- Combination therapy with 5-fluorouracil and pyrimidine nucleosides (thymidine, uridine, cytidine) significantly augmented in vivo antitumor activity in murine models.
- This suggests potential for enhanced efficacy in human tumor xenografts.
Conclusions:
- The nude mouse xenograft model offers a broad range of investigations for cancer drug discovery.
- Combination chemotherapy with pyrimidine nucleosides and 5-fluorouracil warrants further investigation for treating human tumors.
- Aligning preclinical xenograft studies with clinical applications is crucial for developing new cancer therapies.