Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models.

Abstract	SCH66336 is a p.o.-active, farnesyl protein transferase inhibitor. SCH66336 inhibits farnesylation of RAS and other proteins in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. SCH58500 is a replication-deficient, recombinant adenovirus, which expresses the human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and enhanced activity in combination with many chemotherapeutic drugs. Here we report that combination therapy with SCH66336 and SCH58500 has synergistic or additive antiproliferative effects on a panel of tumor cells lines in vitro. The efficacy of the three-drug combination of SCH66336, SCH58500, and paclitaxel was also examined in vitro. Each two-drug interaction displayed such marked synergy, the addition of a third drug to the statistical model could only yield additivity. Greater combined efficacy for SCH66336 and SCH58500 was also observed in vivo in the DU-145 human prostate and wap-ras/F transgenic mouse cancer models.
Authors	L L Nielsen, B Shi, G Hajian, B Yaremko, P Lipari, E Ferrari, M Gurnani, M Malkowski, J Chen, W R Bishop, M Liu
Journal	Cancer research (Cancer Res) Vol. 59 Issue 23 Pg. 5896-901 (Dec 01 1999) ISSN: 0008-5472 [Print] United States
PMID	10606231 (Publication Type: Journal Article)
Chemical References	Piperidines Pyridines Tumor Suppressor Protein p53 Alkyl and Aryl Transferases p21(ras) farnesyl-protein transferase lonafarnib Paclitaxel
Topics	Adenocarcinoma Adenoviruses, Human Alkyl and Aryl Transferases (antagonists & inhibitors) Animals Antineoplastic Combined Chemotherapy Protocols (therapeutic use, toxicity) Breast Neoplasms Cell Survival Drug Synergism Female Genes, ras Humans Male Mice Mice, Nude Mice, SCID Mice, Transgenic Ovarian Neoplasms Paclitaxel (administration & dosage) Pancreatic Neoplasms Piperidines (administration & dosage, therapeutic use, toxicity) Prostatic Neoplasms (drug therapy, pathology) Pyridines (administration & dosage, therapeutic use, toxicity) Teratocarcinoma Tumor Cells, Cultured Tumor Suppressor Protein p53 (administration & dosage, therapeutic use, toxicity)

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