IMPLICATION OF CELL KINETIC CHANGES DURING THE PROGRESSION OF HUMAN PROSTATIC-CANCER

The daily percentage of cells proliferating and dying were determined for normal, premalignant, and cancerous prostatic cells within the pro state as well as for prostatic cancer cells in lymph node, soft tissue , and bone metastases from untreated and hormonally failing patients, These data demonstrate that normal prostatic glandular cells have an e xtremely low but balanced rate of cell proliferation and death (i,e., both < 0.20%/day), This results in a steady-state, self-renewing condi tion in which there is no net growth, although the glandular cells are continuously being replaced (i.e., turnover) every 500 +/- 79 days, T ransformation of these cells into high-grade prostatic intraepithelial neoplastic cells initially involves an unbalanced increase in the dai ly percentage of cells proliferating versus dying, such that net conti nuous growth occurs (i.e,, mean doubling time, 154 +/- 22 days), As th ese early proliferation lesions continue to grow into late stage high- grade prostatic intraepithelial neoplastic cells, the daily percentage of cells dying increases further to a point equaling the daily percen tage of proliferation, This results in cessation of net growth while i nducing a 6-fold increase in the turnover time of these cells (i.e., 5 6 +/- 12 days), increasing their risk of further genetic changes, The transition of late stage high-grade prostatic intraepithelial neoplast ic cells into localized prostatic cancer cells involves no further inc rease in proliferation but a decrease in death resulting in net contin uous growth of localized prostatic cancers with a mean doubling time o f greater than or equal to 475 days, As compared to localized prostati c cancer cells, metastatic prostatic cancer cells within lymph nodes o r bones of untreated patients have an increase in daily rate of prolif eration coupled with a reduction in their daily percentage of cell dea th, producing net growth rates with a mean doubling time of 33 +/- 4 d ays and 54 +/- 5 days, respectively, Remarkably, there is no further i ncrease in proliferation in hormonally failing patients, but instead a n increase in the daily percentage of androgen-independent prostatic c ancer cells dying within soft tissue or bone metastases, These changes result in doubling times which are two to three times longer (le., 12 6 +/- 21 and 94 +/- 15 days) in these lymph node and bone metastatic s ites, respectively, compared to similar sites in hormonally untreated patients, These data demonstrate that the daily percentage of prolifer ation for either androgen-dependent or -independent metastatic prostat ic cancer cells is remarkably low (i.e,, < 3.0%/day), consistent with why antiproliferative chemotherapy has been of such limited value agai nst such metastatic cells, These results also suggest that prostatic c arcinogenesis starts in the second to third decade of life and may req uire over 50 years for progression to pathologically detectable metast atic disease.