Androgen-dependent and -independent human prostate xenograft tumors as models for drug activity evaluation.
The present study evaluated three human prostate xenograft tumors (CWR22, CWR22R, and CWR91) as models for drug activity evaluation. The chemosensitivity and the expression of several proteins (i.e., p-glycoprotein or Pgp, prostate specific antigen or PSA, p53, and Bcl-2) in xenograft tumors were compared with those in patient tumors obtained through radical prostatectomy (n = 26). CWR22 is androgen-dependent, CWR22R is the androgen-independent subline of CWR22, and CWR91 is a separately derived androgen-independent tumor. The results of immunohistochemical and/or Western blot analysis indicate that the expression of PSA, Pgp, p53, and Bcl-2 in the three CWR xenograft tumors are representative of their expression in 100, 85, 90, and 60%, respectively, of patient tumors. The responses of histocultures of xenograft tumors to doxorubicin and paclitaxel, including inhibition of DNA precursor incorporation and cell death induction, were qualitatively similar to the responses of patient tumors. For example, in all three xenograft and patient tumors, doxorubicin produced complete antiproliferation and cytotoxicity (ie., cell kill) whereas paclitaxel produced incomplete effects. A comparison of the concentration-effect relationships in xenograft and patient tumors (population median values) indicates that the chemosensitivity observed in patient tumors is represented by the chemosensitivity of one or more of the three xenograft tumors, as follows: (a) the three xenograft tumors and patient tumors responded equally to doxorubicin-induced antiproliferation; (b) CWR22R, CWR91 and patient tumors responded equally to doxorubicin-induced cytotoxicity, whereas CWR22 was 2-3-fold less sensitive; (c) CWR22 and CWR22R tumors were less sensitive 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 cytotoxicity, whereas CWR91 was 2-3-fold more sensitive. The results of this study indicate that the three xenograft tumors, which show chemosensitivity comparable with the results of > or =50% patient tumors and encompass the majority of the heterogeneous patient prostate tumors in the expression of Pgp, PSA, p53 and Bcl-2 proteins, are useful models for drug activity evaluation.
Chen
C T
CT
College of Pharmacy, The Ohio State University, Columbus 43210, USA.
Gan
Y
Y
Au
J L
JL
Wientjes
M G
MG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000032:analysis*; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D017430:Prostate-Specific Antigen; D017239:Paclitaxel