ABSTRACT
A c-Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose-limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT-observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC0-12 and Cmax ) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia-related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Pyrrolidinones/pharmacokinetics , Pyrrolidinones/therapeutic use , Quinolines/pharmacokinetics , Quinolines/therapeutic use , Administration, Oral , Aged , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Asian People , Capsules , Carcinoma, Hepatocellular/genetics , Cytochrome P-450 CYP2C19/genetics , Female , Humans , Liver Neoplasms/genetics , Male , Middle Aged , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyrrolidinones/administration & dosage , Pyrrolidinones/adverse effects , Quinolines/administration & dosage , Quinolines/adverse effects , Tablets , Treatment OutcomeABSTRACT
Transforming growth factor-ß1 (TGFß1) plays a pivotal role in fibrosis in various organs including the lung. Following pulmonary injury, TGFß1 stimulates conversion of fibroblasts to myofibroblasts that are mainly characterized by up-regulation of α-smooth muscle actin (αSMA) expression, and the resulting excess production of extracellular matrix proteins causes fibrosis with loss of alveolar function. The present study was undertaken to define the role of the sphingosine-1-phosphate (S1P) pathway in TGFß1-induced expression of αSMA in human fetal lung fibroblasts, HFL1 cells. Analysis of mRNA revealed the existence of S1P(1), S1P(2), and S1P(3) receptor mRNAs. Treatment with TGFß1 increased sphingosine kinase (SphK) activity and S1P(3) receptor mRNA at 24h after stimulation, and pharmacological data showed the involvement of sphingomyelinase, SphK, and S1P(3) receptor in the TGFß1-induced up-regulation of αSMA with and without serum. Treatment with pertussis toxin and S1P(1) receptor antagonist W146 enhanced αSMA expression by TGFß1/serum, and S1P decreased and increased αSMA levels with and without serum, respectively. TGFß1 increased cyclooxygenase-2 expression in a manner dependent on serum and the sphingomyelinase/SphK pathway, and the response was decreased by pertussis toxin. Prostaglandin E(2), formed by TGFß1/serum stimulation, decreased the TGFß1-induced expression of αSMA via EP prostanoid receptor. These data suggest that S1P formed by TGFß1 stimulation has diverse effects on the expression of αSMA, inhibition via the S1P(1) receptor-mediated and serum-dependent expression of cyclooxygenase-2 and the resulting formation of prostaglandin E(2), and stimulation via the S1P(3) receptor in a serum-independent manner.
Subject(s)
Actins/metabolism , Fibroblasts/drug effects , Lysophospholipids/metabolism , Sphingosine/analogs & derivatives , Transforming Growth Factor beta1/pharmacology , Arachidonic Acid/metabolism , Cell Line , Cyclic AMP/metabolism , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Fibroblasts/metabolism , Humans , Lung/cytology , RNA, Messenger/metabolism , Receptors, Lysosphingolipid/genetics , Sphingosine/metabolismABSTRACT
Increases in the level of cyclooxygenase (COX)-2 and prostanoids such as prostaglandin E(2) (PGE(2)) are considered biomarkers of colorectal cancer. Therefore, non-steroidal anti-inflammatory drugs (NSAID) have been used to reduce the risk of cancer development by reducing prostanoid biosynthesis as COX inhibitors. Along with their activity as COX inhibitors, NSAID have been reported to have other effects. One major NSAID, indomethacin, has been shown to have several effects independent of COX inhibition. To further examine the COX-inhibition-independent effects of indomethacin on colorectal cancer, we used human colon cancer LS174T cells, known to have express little COX-2 and have no detectable PGE(2) production. Here we show that indomethacin has a potential antagonizing effect on human EP(2) receptors. We believe this study raises the reasons to use indomethacin as a lead-compound for setting up another EP(2) receptor-specific antagonist as a relatively cost-efficient strategy for anti-cancer medication in the future.
