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

Clinical Cancer Research

Volumn 3, Issue 4, 1997, Pages 537-543

  Schwartz, Gary K ^a   Ward, David ^b   Saltz, Leonard ^a   Casper, Ephraim S ^a   Spiess, Tara ^a   Mullen, Eillen ^a   Woodworth, Jim ^b   Venuti, Robert ^b   Zervos, Peter ^b   Storniolo, Anne Marie ^b   Kelsen, David P ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DOXORUBICIN; PROTEIN KINASE C INHIBITOR; SAFINGOL;

ADULT; AGED; ANGIOSARCOMA; ARTICLE; BLOOD TOXICITY; CARCINOMA; CLINICAL ARTICLE; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG HALF LIFE; FEMALE; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; MALE; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL;

ADULT; AGED; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; DOSE-RESPONSE RELATIONSHIP, DRUG; DOXORUBICIN; DRUG ADMINISTRATION SCHEDULE; ENZYME INHIBITORS; FEMALE; HUMANS; INFUSIONS, INTRAVENOUS; LEUKOPENIA; MALE; METABOLIC CLEARANCE RATE; MIDDLE AGED; NEOPLASMS; PILOT PROJECTS; PROTEIN KINASE C; REGRESSION ANALYSIS; SPHINGOSINE; THROMBOCYTOPENIA;

EID: 0030905826     PISSN: 10780432     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (22)

1. Kikkawa, U., and Nishizuka, Y. The role of protein kinase C in transmembrane signalling. Annu. Rev. Cell Biol., 2: 149-178, 1986.
2. Bell, R. M. Protein kinase C activation by diacylglycerol second messengers. Cell, 45: 631-632, 1986.
3. Preiss, J., Loomis, C. R., Bishop, W. R., Stein, R., Niedel, J. E., and Bell, R. M. Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes and ras- and sis-transformed normal rat kidney cells. J. Biol. Chem., 261: 8597-8600, 1986.
4. Smart, R. C., Huang, M. T., and Conney, A. H. sn-1,2-Diacylglycerols mimic the effects of 12-0-tetradecanoylphorbol-13-acetate in vivo by inducing biochemical changes associated with tumor promotion in mouse epidermis. Carcinogenesis (Lond.), 7: 1865-1870, 1986.
5. Persons, D. A., Wilkison, W. O., Bell, R. M., and Finn, O. J. Altered growth regulation and enhanced tumorigenicity of NIH 3T3 fibroblasts transfected with protein kinase C-1 cDNA. Cell. 52: 447-458, 1988.
6. Schwartz, G. K., Haimovitz-Friedman, A., Dhupar, S. K., Ehleiter, D., Maslak, P., Loganzo, F., Kelsen, D. P., Fuks, Z., and Albino, A. P. Potentiation of apoptosis by treatment with the protein kinase C specific inhibitor safingol in mitomycin-C treated gastric cancer cells. J. Natl. Cancer Inst., 8: 1394-1399, 1995.
7. Sachs, C. W., Safa, A., Harrison, S., and Fine, R. L. Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C. J. Biol. Chem., 270: 26639-26648, 1995.
8. Adams, L. M., Cofield, D. J., Seldin, J. C., Kitchen, P. A., Harrison, S. D., and Darges, J. W. Effect of the protein kinase C (PKC) inhibitor SPC-100270 on drug accumulation and cytotoxicity in drug resistant and sensitive tumor cells in vitro. Proc. Am. Assoc. Cancer Res., 34: 410, 1993.
9. Adams, L. M., Dykes, D., Harrison, S. D., Saleh, J., and Saah, L. Combined effect of the chemopotentiator SPC-100270, a protein kinase C inhibitor, and doxorubicin or cisplatin (Cis) on murine isografts and human tumor xenografts. Proc. Am. Assoc. Cancer Res., 34: 410, 1993.
10. Siemann, D. W., Jiang, J. B., Ballas, L., and Janzen, W. Threodihydrosphingosine potentiates the in vivo antitumor efficacy of cisplatin and Adriamycin. Proc. Am. Assoc. Cancer Res., 34: 411, 1993.
11. Susick, R. L., Bozigian, H. P., Kurtzberg, J., Adams, L. M., Weiler, M. S., Harrison, S. D., and Kedderis, L. B. Combination toxicology studies with the chemopotentiating agent SPC-100270 (a PKC inhibitor) and chemotherapeutic agent. Proc. Am. Assoc. Cancer Res., 34: 410, 1993.
12. Rajewsky, R. A., Kosednar, D. G., Matches, T. A., Wong, O. S., Burchett, K., and Thakker, K. Stereo-specific analysis of a novel protein kinase C inhibitor. J. Pharm. Biomed. Anal., 13: 247-253, 1995.
13. Pierce, R. N., and Jatlow, P. I. Measurements of Adriamycin (doxorubicin) and its metabolites in human plasma using reversed-phase high performance liquid chromatography and fluorescence detection. J. Chromatogr., 704: 471-478, 1979.
14. Gibaldi, M., and Perrier, D. Pharmacokinetics, Ed. 2, pp. 409-416. New York: Marcel Dekker, 1982.
15. Kikkawa, U., Kishimoto, A., and Nishizuka, Y. The protein kinase C family: heterogeneity and its implications. Annu. Rev. Biochem., 58: 31-44, 1989.
16. Coussens, L., Parker, P. J., Rhee, L., Yang-Feng, T. L., Chen, E., Waterfield, M. D., Franke, U., and Ullrich, A. Multiple, distinct forms of bovine and human PKC suggests diversity in cellular signaling pathways. Science (Washington DC), 233: 859-866, 1986.
17. Hannun, Y. A., Loomis, C. R., Merrill, A. H., Jr., and Bell, R. M. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J. Biol. Chem., 267: 12602-12609, 1986.
18. Nakano, H., Kobayashi, E., Takahashi, I., Tamaoki, T., Kuzuu, Y., and Iba, H. Staurosporine inhibits tyrosine-specified protein kinase activity of Rous sarcoma virus transforming protein. J. Antibiot. (Tokyo), 40: 706-708, 1987.
19. Tamaoki, T., and Nakano, H. Potent and specific inhibitors of PKC or microbial origin. Biotechnology, 8: 732-735, 1990.
20. Bozigian, H., Teo, S., Kleeman, J., Brisson, J., and Harrison, S. D. Comparison of the pharmacokinetics of SPC-100270, a protein kinase C inhibitor in mice, following administration of toxic and therapeutic doses. Proc. Am. Assoc. Cancer Res., 34: 410, 1993.
21. Kedderis, L. B., Weiler, M. S., Christian, B. J., Thomford, P. J., Hall, R. L., Salamon, C. M., Harrison, S. D., and Susick, R. L. Preclinical safety assessment of SPC-100270 emulsion, a novel protein kinase C inhibitor under development for the use as a chemopotentiation agent. Proc. Am. Assoc. Cancer Res., 34: 410, 1993.
22. Jacquet, J-M., Bressolle, F., Gaitier, M., Bourrier, M., Donadio, D., Jourdan, J., and Rossi, J-F. Doxorubicin and doxorubicinol: intra and inter-individual variations of pharmacokinetic parameters. Cancer Chemother. Pharmacol., 27: 219-225, 1990.