Establishment of human primary colorectal tumor xenograft models to test anticancer drugs.

Abstract

e14121 Background: Human xenograft tumor models established by transplantation of human tumor cell lines into immunodeficient mice have been routinely used for preclinical testing anticancer agents. However, such tumor models have a relatively low transplantability and limited correlation with clinical findings. Recently, we have developed human primary colorectal tumor xenograft models by transplanting fresh human colorectal tumor tissues into nude mice, which is being used to test standard chemotherapeutic drugs and to screen effectiveness of novel compounds. Methods: The fresh colorectal tumor fragments of 2-3 mm were subcutaneously implanted in the flanks of nude mice. Sixteen tumor fragments were grafted into four mice from one patient tumor tissue. In the first passage, tumors derived from male patients were implanted into male mice, and tumors from women were inoculated into female mice. All therapeutic efficacy experiments used female mice. The test drugs included 5-FU, irinotecan, and oxaliplatin. Results: A total of 36 human colorectal tumor samples were initially implanted with 14 successful xenograft tumors (39%) from the first passage. The rate of tumor formation was higher in the second and third passages, ranging from approximately 80%-100%. The three anticancer drugs' efficacy data showed that 5-FU produced 35%-48% tumor growth inhibition, irinotecan 57%-86%, and oxaliplatin 68%-89%, which are consistent with clinical findings. The human primary colorectal tumor xenografts' architecture, biomarker profile and histopathologic morphology from three generations reproduced biological activity and response to therapy of the original tumors. Conclusions: Human primary colorectal tumor models have been used to test current chemotherapeutic agents. Future studies testing effectiveness of novel compounds against human colon cancer tumors are under way using this experimental model. This strategy may predict more relevant clinical response rates and higher correlation with clinical findings than use of traditional xenograft models established from long-term cultured cancer cell lines. Furthermore, they have advantages for test of target-oriented therapeutics in new drugs development programs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmaron