Flavopiridol (L86-8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells.
We have selected a panel of human tumor xenografts for in vitro and in vivo studies that allows an indication of selectivity of action of novel chemotherapeutic agents. We report here the antitumor activity of the flavone flavopiridol (previously designated L86-8275), which has been selected for further studies based in part on its behavior in the anticancer drug screening system of the United States National Cancer Institute. Eighteen human tumor and five cell line-derived xenografts established by serial passage in nude mice in our laboratory were used as tumor models for in vitro investigations using a modified double-layer soft agar assay. In vivo investigations were completed in nude mice bearing advanced-stage s.c. growing prostate cancer xenografts. Antitumor activity in vitro (test/control </= 30%) of flavopiridol was observed at the very low concentration of 0.1 ng/ml in three of four prostatic xenografts and in one melanoma xenograft. Overall, in 14 of 23 (61%) tumor xenografts, drug treatment resulted in a IC70 of <10 ng/ml, demonstrating the high antiproliferative potential of flavopiridol. Toxicity to in vitro bone marrow cultures was evident only at 100 ng/ml, indicating potential high selectivity for susceptible tumor cells. Comparison of tumor cells with bone marrow samples tested showed clear prostate carcinoma and moderate melanoma selectivity. In vivo studies of flavopiridol confirmed antitumor activity in both prostate cancer xenografts investigated. At the maximal tolerated dose of 10 mg/kg/day administered p.o. on days 1-4 and 7-11, flavopiridol effected tumor regression in PRXF1337 and tumor stasis lasting for 4 weeks in PRXF1369. We conclude that flavopiridol shows strong prostate-and moderate melanoma-specific antitumor activity in vitro. The prostate antitumor activity is also reflected by the two in vivo models studied. Initial clinical efforts with flavopiridol might consider early evaluation in patients with prostate carcinoma.
Drees
M
M
Department of Internal Medicine, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
Dengler
W A
WA
Roth
T
T
Labonte
H
H
Mayo
J
J
Malspeis
L
L
Grever
M
M
Sausville
E A
EA
Fiebig
H H
HH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003114:Colony-Forming Units Assay; D004354:Drug Screening Assays, Antitumor; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib