PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy.
Treatment of solid tumors with combinations of chemotherapeutic agents has not led to significant increases in long-term survival. Recent studies support a role for inhibitors of checkpoint arrest as a means to enhance the cytotoxicity of chemotherapy. We have shown previously that triptolide (PG490), an oxygenated diterpene derived from a Chinese medicinal plant, induces apoptosis in cultured tumor cells and sensitizes tumor cells to topoisomerase inhibitors by blocking p53-mediated induction of p21. Here we extend our studies to a tumor xenograft model and evaluate the efficacy and safety of PG490-88 (14-succinyl triptolide sodium salt), a water-soluble prodrug of PG490. We also look at the combination of PG490 or PG490-88 with CPT-11, a topoisomerase I inhibitor, in cultured cells and in the tumor xenograft model. We show that PG490-88 is a safe and potent antitumor agent when used alone, causing tumor regression of lung and colon tumor xenografts. We also show that PG490-88 acts in synergy with CPT-11 to cause tumor regression. A phase I trial of PG490-88 for solid tumors began recently and safety and optimal dosing data should accrue within the next 12 months. Our findings that PG490-88 causes tumor regression and that it acts in synergy with DNA-damaging chemotherapeutic agents suggest a role as an antineoplastic agent and chemosensitizer for the treatment of patients with solid tumors.
Fidler
John M
JM
Pharmagenesis, Inc., Palo Alto, CA, USA.
Li
Ke
K
Chung
Cathie
C
Wei
Ke
K
Ross
Jessica A
JA
Gao
Mingxing
M
Rosen
Glenn D
GD
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004224:Diterpenes / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010616:Phenanthrenes / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004224:Diterpenes; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D010616:Phenanthrenes; D016159:Tumor Suppressor Protein p53; C001899:triptolide; D000077146:Irinotecan; C417603:omtriptolide; D002166:Camptothecin