Establishment of human prostate tumor xenografts in nude mice and response to 9-nitrocamptothecin in vivo and in vitro does not correlate with the expression of various apoptosis-regulating proteins.
Flow cytometry and microscopy analyses have demonstrated that 9-nitrocamptothecin (9NC) induces apoptosis in prostate carcinoma LNCaP, DU-145 and PC-3 cells grown in culture or as xenografts. 9NC induces apoptosis regardless of the ability of the cells to induce tumors following xenografting into nude mice. Detection of apoptosis by flow cytometry was preceded or accompanied by increased cell size, loss of nuclear structure and vacuolization, as the tumor regressed, but no visible chromatin fragmentation. This is the first demonstration that 9NC is curative for human prostate carcinoma xenografts in the nude mouse model in the absence of detectable drug-induced toxicity during and after tumor regression. These findings indicate that 9NC may develop into a chemotherapeutic drug for the effective treatment of prostate cancer patients. Further, there was no apparent correlation of the steady-state level of the apoptosis-regulating proteins, Bcl-2, Bcl-XL, Bax and Ich-1, with tumorigenicity of the prostate cells xenografted in nude mice, aggressiveness of tumors grown in nude mice, and induction of apoptosis by 9NC. However, the TIAR protein was present at markedly high levels in all prostate carcinoma cell lines and this may correlate with their susceptibility to 9NC-induced apoptosis.
Pantazis
P
P
Stehlin Foundation for Cancer Research, St. Joseph Hospital, Houston, TX, USA.
Chatterjee
D
D
Wyche
J
J
DeJesus
A
A
Early
J
J
Plaschke
S
S
Giovanella
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D014183:Transplantation, Heterologous / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C079905:rubitecan; D002166:Camptothecin