Clinical Cancer Research, Vol 3, Issue 4 537-543, Copyright © 1997 by American Association for Cancer Research

ARTICLES

A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin

GK Schwartz, D Ward, L Saltz, ES Casper, T Spiess, E Mullen, J Woodworth, R Venuti, P Zervos, AM Storniolo and DP Kelsen
Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Section, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. USA.

We performed a pilot clinical trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-week intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those associated with potentiation of DOX in animals. The mean Cmax and area under the curve for safingol at the 120 mg/m2 dose level were 1040 +/- 196 ng/ml and 1251 +/- 317 mg x h/ml, respectively. The mean plasma half-life for safingol was 3.97 +/- 2.51 h, the mean estimated clearance was 3140 +/- 765 ml/min, and the mean volume of distribution was of 995 +/- 421 liters. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were observed in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot Phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacologically active without dose-limiting toxicity.

This article has been cited by other articles:

				S. T. Pruett, A. Bushnev, K. Hagedorn, M. Adiga, C. A. Haynes, M. C. Sullards, D. C. Liotta, and A. H. Merrill Jr. Thematic Review Series: Sphingolipids. Biodiversity of sphingoid bases ("sphingosines") and related amino alcohols J. Lipid Res., August 1, 2008; 49(8): 1621 - 1639. [Abstract] [Full Text] [PDF]

				K. Takabe, S. W. Paugh, S. Milstien, and S. Spiegel "Inside-Out" Signaling of Sphingosine-1-Phosphate: Therapeutic Targets Pharmacol. Rev., June 1, 2008; 60(2): 181 - 195. [Abstract] [Full Text] [PDF]

				D. E. Modrak, D. V. Gold, and D. M. Goldenberg Sphingolipid targets in cancer therapy. Mol. Cancer Ther., February 1, 2006; 5(2): 200 - 208. [Abstract] [Full Text] [PDF]

				E. A. Sausville Indifferently Pursued or Unowned Drugs: Who Should Lead Where Companies Do Not Tread? J. Clin. Oncol., March 20, 2005; 23(9): 1796 - 1798. [Full Text] [PDF]

				S. Batra, C. P. Reynolds, and B. J. Maurer Fenretinide Cytotoxicity for Ewing's Sarcoma and Primitive Neuroectodermal Tumor Cell Lines Is Decreased by Hypoxia and Synergistically Enhanced by Ceramide Modulators Cancer Res., August 1, 2004; 64(15): 5415 - 5424. [Abstract] [Full Text] [PDF]

				C. R. Johnson, J. Chun, R. Bittman, and W. D. Jarvis Intrinsic Cytotoxicity and Chemomodulatory Actions of Novel Phenethylisothiocyanate Sphingoid Base Derivatives in HL-60 Human Promyelocytic Leukemia Cells J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 452 - 461. [Abstract] [Full Text] [PDF]

				M. Dragusin, C. Gurgui, G. Schwarzmann, J. Hoernschemeyer, and G. van Echten-Deckert Metabolism of the unnatural anticancer lipid safingol, L-threo-dihydrosphingosine, in cultured cells J. Lipid Res., September 1, 2003; 44(9): 1772 - 1779. [Abstract] [Full Text] [PDF]

				J. A. Shabbits, Y. Hu, and L. D. Mayer Tumor Chemosensitization Strategies Based on Apoptosis Manipulations Mol. Cancer Ther., August 1, 2003; 2(8): 805 - 813. [Full Text] [PDF]

				A. B. da Rocha, D.R.A. Mans, A. Regner, and G. Schwartsmann Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas? Oncologist, February 1, 2002; 7(1): 17 - 33. [Abstract] [Full Text] [PDF]

				E. M. Schmelz, P. C. Roberts, E. M. Kustin, L. A. Lemonnier, M. C. Sullards, D. L. Dillehay, and A. H. Merrill Jr. Modulation of Intracellular {beta}-Catenin Localization and Intestinal Tumorigenesis in Vivo and in Vitro by Sphingolipids Cancer Res., September 1, 2001; 61(18): 6723 - 6729. [Abstract] [Full Text] [PDF]

				P. Dent and S. Grant Pharmacologic Interruption of the Mitogen-activated Extracellular-regulated Kinase/Mitogen-activated Protein Kinase Signal Transduction Pathway: Potential Role in PromotingCytotoxic Drug Action Clin. Cancer Res., April 1, 2001; 7(4): 775 - 783. [Full Text]

				B. J. Maurer, L. Melton, C. Billups, M. C. Cabot, and C. P. Reynolds Synergistic Cytotoxicity in Solid Tumor Cell Lines Between N-(4-Hydroxyphenyl)retinamide and Modulators of Ceramide Metabolism J Natl Cancer Inst, December 6, 2000; 92(23): 1897 - 1909. [Abstract] [Full Text] [PDF]