Growth of human prostate carcinomas with and without hormone alpha-dehydrotestosterone in nude mice

Objectives: The dependence of human prostate carcinoma growth on hormone was studied in xenotransplants in nude mice. The objective was to determine differences in cell kinetic parameters and volume growth of tumors growing with alpha-dehydrotestosterone (alpha DHT) and without alpha DHT. These differences could be used as arguments pro and contra the adaptation versus the clonal selection hypothesis. Methods: Human prostate carcinomas were xenotransplanted into nude mice. Growth of tumors was observed in castrated male mice without and with implanted osmotic pumps secreting alpha DHT. In a further series of experiments the alpha DHT tubes were removed when the tumors had reached a volume of 0.3 cm(3). Tumor volume was measured to determine tumor doubling time with and without alpha DHT. Detailed cell kinetics were analyzed using the bromodeoxyuridine (BrdUrd) method with flow cytometry. Applying the relative movement (RM) and a simulation analysis to parallel single and multiple BrdUrd labelling experimental data we determined transit times through the phases of cell cycle, potential doubling time T-pot, growth fraction (GF) and cell loss. Results: Five human prostate carcinomas were xenotransplanted into nude mice. Tumor take was only achieved when androgen hormone was present. However, when alpha DHT was removed when the tumors had grown to a volume of 0.3 cm(3), they continued to grow at nearly the same T-d as those tumors with continued alpha DHT application. The BrdUrd experiments, on the other hand, showed considerable increase of T-c and T-pot upon withdrawal of aDHT in 4 out of 5 tumors. The GF and labelling index (LI) were maintained at about the same level as alpha DHT consuming tumors. Conclusion: While small transplanted tumor pieces do not grow without alpha DHT, larger tumors grow with the same T-d after removal of alpha DHT. The slower proliferation shown by the increased T-c and T-pot is balanced by less cell loss. Since GF and LI were maintained at about the same level, we conclude that in our tumors the majority of cells adapted to hormone independence. There was no evidence for the selection model since the tumors continued to grow at about the same speed after hormone depletion. All cell kinetic parameters showed a considerable inter- and intratumoral heterogeneity. A clinical implication may be that hormone ablation therapy should always be supplemented by some other therapy.