[Sensitivity of UCN-01 lies in the balance of CDK 2 kinase and p21].
Five human cancer cell lines (MKN 45, HT-29, WiDr, PAN-3-JCK, and CRL 1420) were used to evaluate the antitumor spectrum of UCN-01, which suppressed the growth of these digestive cancer cell lines. A human pancreatic cancer xenograft (CRL 1420) and breast cancer xenograft (MX-1) were used to determine their sensitivity to UCN-01, in nude mice. UCN-01 significantly suppressed the tumor growth of CRL 1420 at a dose of 10 mg/kg in a schedule of (qd x 5) x 2, but was ineffective for MX-1. While p21 protein expression was induced by UCN-01 in both CRL 1420 and MX-1, an accumulation of dephosphorylated ppRb was observed only in CRL 1420, resulting in G1 block as detected by flow cytometric analysis. The CDK 2 activity of MX-1 was almost 6 times higher than that of CRL 1420, which might account for the resistance of MX-1 to UCN-01 in spite of the induction of p21 in this strain. We conclude that the determinant of sensitivity to UCN-01 lies in the balance of CDK 2 kinase activity and p21 protein induction.
Abe
S
S
Dept. of Surgery, Haga Red Cross Hospital.
Kubota
T
T
Otani
Y
Y
Furukawa
T
T
Watanabe
M
M
Kumai
K
K
Kitajima
M
M
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000470:Alkaloids; C054852:7-hydroxystaurosporine; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D019311:Staurosporine