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¹ Pharmagenesis, Inc., Palo Alto, CA; ² Department of Medicine, Stanford University Medical School, Stanford, CA; and ³ Applied Biosystems, Foster City, CA

Requests for reprints: Glenn D. Rosen, Pulmonary and Critical Care Medicine, Stanford University Medical School, 300 Pasteur Drive, Stanford, CA 94305-5236. Phone: (650) 725-9536; Fax: (650) 725-4071. E-mail: grosen{at}stanford.edu

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.

Key Words: Cancer • triptolide • chemosensitizer • xenograft • p53

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support: Pharmagenesis and an ALA Career Investigator Award to G.D.R.

Note: J.M. Fidler, K. Li, and C. Chung contributed equally to the work presented in this manuscript. J. M. Fidler and K. Li contributed to the in vitro tumor biology studies.

¹ K. Wei and G. D. Rosen, unpublished results.

² C. Chung and G. D. Rosen, unpublished results.

³ K. Li, C. Chung, J. Fidler, and G. D. Rosen, unpublished results.

⁴ K. Wei and G. D. Rosen, Unpublished results.

⁵ M. Gao and G. D. Rosen, unpublished results.

⁶ M. Gao and G. D. Rosen, unpublished results and personal communication from Dr. Marty Mayo, University of Virginia.

⁷ W. Chang and G. D. Rosen, unpublished results.

⁸ M. Gao and G. D. Rosen, unpublished results.

Received 2/ 6/03; revised 5/ 9/03; accepted 6/17/03.