Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program.

Abstract

BACKGROUND:

SCH 727965 is a novel drug in clinical development that potently and selectively inhibits CDK1, CDK2, CDK5, and CDK9. The activity of SCH 727965 was evaluated against the PPTP's in vitro and in vivo panels.

PROCEDURES:

SCH 727965 was tested against the PPTP in vitro panel using 96 hours exposure at concentrations ranging from 0.1 nM to 1.0 µM. It was tested against the PPTP in vivo panels at a dose of 40 mg/kg administered intraperitoneally twice weekly for 2 weeks and repeated at Day 21 with a total observation period of 6 weeks.

RESULTS:

The median IC(50) value for the cell lines was 7.5 nM, with less than fourfold range between the minimum (3.4 nM) and maximum (11.2 nM) IC(50) values. SCH 727965 demonstrated an activity pattern consistent with cytotoxicity for most of the cell lines. Forty-three xenograft models were studied and SCH 727965 induced significant delays in event free survival distribution compared to control in 23 of 36 (64%) evaluable solid tumor xenografts and in 3 of 7 ALL xenografts. SCH 727965 did not induce objective responses in the solid tumor panels and the best response observed was stable disease for one osteosarcoma xenograft. In the leukemia panel, there were two objective responses with a complete response observed in a single xenograft.

CONCLUSIONS:

SCH 727965 shows an interesting pattern of activity suggesting its potential applicability against selected childhood cancers, particularly leukemias.

• Authors: Richard Gorlick, E Anders Kolb, Peter J Houghton, Christopher L Morton, Geoffrey Neale, Stephen T Keir, Hernan Carol, Richard Lock, Doris Phelps, Min H Kang, C Patrick Reynolds, John M Maris, Catherine Billups, Malcolm A Smith
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 59 Issue 7 Pg. 1266-74 (Dec 15 2012) ISSN: 1545-5017 [Electronic] United States
• PMID: 22315240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Cyclic N-Oxides
• Indolizines
• Pyridinium Compounds
• dinaciclib
• Cyclin-Dependent Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Child
• Cyclic N-Oxides
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Disease-Free Survival
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Female
• Humans
• Indolizines
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Mice, SCID
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy)
• Pyridinium Compounds (pharmacokinetics, therapeutic use)
• Xenograft Model Antitumor Assays