Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites.
Many anticancer agents damage DNA and arrest cell-cycle progression primarily in S or G(2) phase of the cell cycle. Previous studies with the topoisomerase I inhibitor SN38 have shown the efficacy of the Chk1 inhibitor UCN-01 to overcome this arrest and induce mitotic catastrophe. UCN-01 was limited in clinical trials by unfavorable pharmacokinetics. SCH900776 is a novel and more selective Chk1 inhibitor that potently inhibits Chk1 and abrogates cell-cycle arrest induced by SN38. Like UCN-01, abrogation of SN38-induced arrest enhances the rate of cell death but does not increase overall cell death. In contrast, SCH900776 reduced the growth-inhibitory concentration of hydroxyurea by 20- to 70-fold. A similar magnitude of sensitization was observed with cytarabine. A 5- to 10-fold sensitization occurred with gemcitabine, but no sensitization occurred with cisplatin, 5-fluorouracil, or 6-thioguanine. Sensitization occurred at hydroxyurea concentrations that marginally slowed DNA replication without apparent activation of Chk1, but this led to dependence on Chk1 that increased with time. For example, when added 18 hours after hydroxyurea, SCH900776 induced DNA double-strand breaks consistent with rapid collapse of replication forks. In addition, some cell lines were highly sensitive to SCH900776 alone, and these cells required lower concentrations of SCH900776 to sensitize them to hydroxyurea. We conclude that some tumors may be very sensitive to the combination of SCH900776 and hydroxyurea. Delayed administration of SCH900776 may be more effective than concurrent treatment. SCH900776 is currently in phase I clinical trials, and these results provide the rationale and schedule for future clinical trials.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
Ryan
R
Montano
Injae
I
Chung
Kristen M
KM
Garner
David
D
Parry
Alan
A
Eastman
D000963:Antimetabolites / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D003561:Cytarabine / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D000077146:Irinotecan; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D000093542:Gemcitabine
D000963:Antimetabolites; D000970:Antineoplastic Agents; C559815:MK-8776; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D003561:Cytarabine; D003841:Deoxycytidine; D000077146:Irinotecan; C054852:7-hydroxystaurosporine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D019311:Staurosporine; D006918:Hydroxyurea; D002166:Camptothecin; D000093542:Gemcitabine