Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models.
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.
Nielsen
L L
LL
Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Shi
B
B
Hajian
G
G
Yaremko
B
B
Lipari
P
P
Ferrari
E
E
Gurnani
M
M
Malkowski
M
M
Chen
J
J
Bishop
W R
WR
Liu
M
M
D000230:Adenocarcinoma; D000260:Adenoviruses, Human; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001943:Breast Neoplasms; D002470:Cell Survival; D004357:Drug Synergism; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D010051:Ovarian Neoplasms; D017239:Paclitaxel / Q000008:administration & dosage; D010190:Pancreatic Neoplasms; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D018243:Teratocarcinoma; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes