The mechanism of chemoprevention by protease inhibitors (PIs) will be tested using nicotinamide, a PI with the unusual property of being a vitamin (vitamin B3). It is also a precursor of the important coenzyme nicotinamide adenine dinucleotide (NAD), which plays a role in DNA repair. Nicotinamide has been shown to inhibit chymotrypsin and trypsin hydrolysis of radioactive casein, with preferential inhibition of chymotrypsin. Nicotinamide, a known inhibitor of poly(ADP)ribose transferase, also suppresses oxygen-radical induction of phorbol ester tumor promoters in neutrophils. Moreover, nicotinamide causes suppression of the oncogene expression similar to that shown by PIs. Nicotinamide is available in pure form at low cost and is nontoxic in humans at high levels. We will test its chemopreventive action in two-stage carcinogenesis studies, and prevention of breast and dimethyl hydrazine-induced colon cancer in mice. The mechanism of the PI chemopreventive action may be due to the protection of nicotinamide and NAD hydrolysis by chymotrypsin-type enzymes increasing the effective NAD available for DNA repair. This will be studied and related to oncogene repression involving deletion of the oncogene, at definite times, and compared to potato inhibitor 1, a chymotrypsin inhibitor. With these experiments, we hope to learn the mechanism for preventing cancer and to identify a nontoxic PI, nicotinamide, available for testing in humans.
| Lim, J S; Frenkel, K; Troll, W (1992) Tamoxifen suppresses tumor promoter-induced hydrogen peroxide formation by human neutrophils. Cancer Res 52:4969-72 |
