Salirasib in the treatment of pancreatic cancer.
The Ras family of genes is involved in the cellular regulation of proliferation, differentiation, cell adhesion and apoptosis. The K-ras gene is mutated in over 90% of pancreatic cancer cases. Salirasib (S-trans,trans-farnesylthiosalycilic acid [FTS]) is a synthetic small molecule that acts as a potent Ras inhibitor. It is a farnesylcysteine mimetic that selectively disrupts the association of active RAS proteins with the plasma membrane. Animal studies demonstrated that salirasib inhibited tumor growth, downregulated gene expression in the cell cycle and Ras signaling pathways. In a clinical study of salirasib combined with standard doses of gemcitabine, it was demonstrated that the two drugs have no overlapping pharmacokinetics. The salirasib recommended dose was 600 mg twice daily and the progression-free survival was 4.7 months. Future studies will determine whether salirasib adds to the anti-tumor activity of drugs approved by the US FDA for pancreatic cancer.
Department of Investigational Cancer Therapeutics, The Phase I Clinical Trials Program, Unit 455, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ernesto
E
Bustinza-Linares
Razelle
R
Kurzrock
Apostolia-Maria
AM
Tsimberidou
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004354:Drug Screening Assays, Antitumor; D005204:Farnesol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D037161:Galectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors; D012459:Salicylates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D037161:Galectins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D003841:Deoxycytidine; D005204:Farnesol; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine