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 α-dehydrotestosterone (αDHT) and without αDHT. 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 αDHT. In a further series of experiments the αDHT tubes were removed when the tumors had reached a volume of 0.3 cm3. Tumor volume was measured to determine tumor doubling time with and without αDHT. 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 Tpot, 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 αDHT was removed when the tumors had grown to a volume of 0.3 cm3, they continued to grow at nearly the same Td as those tumors with continued αDHT application. The BrdUrd experiments, on the other hand, showed considerable increase of Tc and Tpot upon withdrawal of αDHT in 4 out of 5 tumors. The GF and labelling index (LI) were maintained at about the same level as αDHT consuming tumors. Conclusion: While small transplanted tumor pieces do not grow without αDHT, larger tumors grow with the same Td after removal of αDHT. The slower proliferation shown by the increased Tc and Tpot 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.

Keywords:
Tumor growth, Testosterone, Adaptation model, Prostate carcinoma
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