Survival rates of homozygotic knockout rats as a tool for preclinical assessment of cancer prevention and treatment.

BACKGROUND

The gene that encodes tumor protein p53, , is mutated or silenced in most human cancers and is recognized as one of the most important cancer drivers. Homozygotic 53 knockout mice, which develop lethal cancers early in their lives, are already used in cancer prevention studies, and now 53 knockout rats have also been generated. This study assessed feasibility of using homozygous knockout rats to evaluate the possible outcome of cancer chemoprevention.

METHODS

A small colony of 53 knockout rats with a Wistar strain genetic background was initiated and maintained in the animal house at our institution. heterozygotic females were bred with homozygous knockout males to obtain a surplus of knockout homozygotes. To evaluate the reproducibility of their lifespan, 4 groups of homozygous knockout male rats born during consecutive quarters of the year were kept behind a sanitary barrier in a controlled environment until they reached a moribund state. Their individual lifespan data were used to construct quarterly survival curves.

RESULTS

The four consecutive quarterly survival curves were highly reproducible. They were combined into a single "master" curve for use as a reference in intervention studies. The average lifespan of untreated male homozygous knockout rats was normally distributed, with a median of 133 days. Sample size vs. effect calculations revealed that confirming a 20% and 30% increase in the lifespan would respectively require a sample size of 18 and 9 animals (when assessed using the -test with a power of 80% and alpha set at 0.05). As an example, the homozygous knockout rat model was used to test the chemopreventive properties of carnosine, a dipeptide with suspected anticancer properties possibly involving modulation of the mTOR pathway. The result was negative.

CONCLUSION

Further evaluation of the homozygous knockout male rat colony is required before it can be confirmed as a viable tool for assessing new methods of cancer prevention or treatment.