ANDROGEN-DEPENDENT AND ANDROGEN-INDEPENDENT HUMAN PROSTATE XENOGRAFT TUMORS AS MODELS FOR DRUG ACTIVITY EVALUATION

The present study evaluated three human prostate xenograft tumors (CWR 22, CWR22R, and CWR91) as models for drug activity evaluation. The che mosensitivity and the expression of several proteins (i.e., p-glycopro tein or Pgp, prostate specific antigen or PSA, p53, and Bcl-2) in xeno graft tumors were compared with those in patient tumors obtained throu gh radical prostatectomy (n = 26). CWR22 is androgen-dependent, CWR22R is the androgen-independent subline of CWR22, and CWR91 is a separate ly derived androgen-independent tumor. The results of immunohistochemi cal and/or Western blot analysis indicate that the expression of PSA, Pgp, p53, and Bcl-2 in the three CWR xenograft tumors are representati ve of their expression in 100, 85, 90, and 60%, respectively, of patie nt tumors. The responses of histocultures of xenograft tumors to doxor ubicin and paclitaxel, including inhibition of DNA precursor incorpora tion and cell death induction, were qualitatively similar to the respo nses of patient tumors. For example, in all three xenograft and patien t tumors, doxorubicin produced complete antiproliferation and cytotoxi city (i.e., cell kill) whereas paclitaxel produced incomplete effects. A comparison of the concentration-effect relationships in xenograft a nd patient tumors (population median values) indicates that the chemos ensitivity observed in patient tumors is represented by the chemosensi tivity of one or more of the three xenograft tumors, as follows: (a) t he three xenograft tumors and patient tumors responded equally to doxo rubicin-induced antiproliferation; (b) CWR22R, CWR91 and patient tumor s responded equally to doxorubicin-induced cytotoxicity, whereas CWR22 was 2-3-fold less sensitive; (c) CWR22 and CWR22R tumors were less se nsitive to paclitaxel-induced antiproliferation compared with patient tumors, whereas CWR91 was several-fold more sensitive; and (d) CWR22, CWR22R and patient tumors responded equally to paclitaxel-induced cyto toxicity, whereas CWR91 was 2-3-fold more sensitive. The results of th is study indicate that the three xenograft tumors, which show chemosen sitivity comparable with the results of greater than or equal to 50% p atient tumors and encompass the majority of the heterogenous patient p rostate tumors in the expression of Pgp, PSA, p53 and Bcl-2 proteins, are useful models for drug activity evaluation.