Changes in cyclin dependent kinase inhibitors p21 and p27 during the castration induced regression of the CWR22 model of prostatic adenocarcinoma

Purpose: The expression of the cyclin dependent kinase inhibitors p21 and p 27 was examined in prostatic adenocarcinomas following castration. Materials and Methods: Male nude mice inoculated with the androgen dependen t human prostatic tumor CWR22 were castrated when the tumors reached a volu me of 0.8 to 1.1 cm.(3) and were sacrificed at 3, 7, 21, 28 and 42 days pos t-castration. An additional group of mice received a subcutaneous testoster one pellet at 21 days post-castration and was sacrificed at 28 days post-ca stration. The expression of the Ki-67 antigen, p21 and p27 was examined by immunohistochemistry. Results: The mitotic rate as well as the number of Ki-67 antigen positive c ells decreased to 3% of intact control values by 7 days post-castration and were less than 0.01% of intact control values at 21, 28 and 42 days post-c astration. The percentage of p21 expressing cells decreased from 15 +/- 2% in intact controls to less than 1% by 42 days post-castration. In contrast, the percentage of cells that expressed p27 increased from 25 +/- 3% in int act controls to 51 +/- 8% at 3 days post-castration and to 80 to 95% at day s 7, 21, 28 and 42 days post-castration. Testosterone treatment from 21 to 28 days post-castration resulted in an increase in Ki-67 antigen positive c ells to 200% of intact controls and a concomitant reduction in p27 expressi ng cells to about 50% of intact controls. Castration-induced changes in p27 expression were not observed in the CWR22R tumor, a transplantable relapse d derivative of the CWR22 tumor. Conclusion: These findings suggest that p27 expression is regulated negativ ely by androgens and that increased expression of p27 in CWR22 xenografts m ay be involved in the suppression of proliferation following castration.