ABSTRACT
Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal prognosis, but its mechanism of drug resistance is unknown. This study examines whether glutathione S-transferase-pi (GSTP1-1) is involved in resistance to anticancer drugs in cholangiocarcinoma and whether GSTP1-1-specific inhibitors can overcome this resistance. First, immunohistochemical examination disclosed strong staining of all our 17 cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type. Transfection of the GSTP1-1 antisense expression vector into a human cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin (ADR), cisplatin, and alkylating agents such as melphalan and 4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared with that of mock transfectants. We next synthesized GSTP1-1-specific inhibitors by elongating the carbon chain of the ethylester at the N-terminal of gamma-glutamyl-S-benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester (C16C2) showed the smallest volume of central compartment and smallest volume of distribution at steady state and the second smallest clearance, being the most effective inhibitor in vivo. The IC50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1 activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a GSTP1-1-specific inhibitor, is a potent agent against the resistance.
Subject(s)
Antineoplastic Agents/pharmacology , Cholangiocarcinoma/pathology , Drug Resistance, Multiple , Glutathione Transferase/antagonists & inhibitors , Isoenzymes/antagonists & inhibitors , Oligopeptides/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/pathology , Disease Models, Animal , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Glutathione S-Transferase pi , Humans , Immunohistochemistry , Inhibitory Concentration 50 , Liver Neoplasms/pathology , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/prevention & control , Oligopeptides/therapeutic use , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
A 67-year-old female was admitted to our hospital in May, 2001 for examination. She was diagnosed with advanced gastric cancer that was inoperable due to peritoneal dissemination. Seventeen courses of sequential MTX and 5-FU therapy, and 2 courses of TS-1 plus CDDP were carried out. A partial response (PR) and prolonged NC were obtained after these chemotherapies. However, pleural effusion and ascites appeared again, and we diagnosed progressive disease. As a third line chemotherapy for this patient, paclitaxel (TXL) was administered. Treatment consisted of two 3-week courses of paclitaxel 70 mg per m2 on day 1 of each week, with a 1-week break between the courses. Two weeks after the start of this therapy, pleural effusion and ascites had completely disappeared. Paclitaxel is considered to be promising for advanced gastric cancers, as second or third line chemotherapy with paclitaxel for patients with inoperable gastric cancer seems to be effective in improving QOL.
Subject(s)
Adenocarcinoma, Scirrhous/drug therapy , Antineoplastic Agents, Phytogenic/administration & dosage , Paclitaxel/administration & dosage , Stomach Neoplasms/drug therapy , Aged , Ascites/drug therapy , Drug Administration Schedule , Female , Humans , Pleural Effusion/drug therapyABSTRACT
A 43-year-old woman was admitted for examination of fever, an elevated transaminase level, LDH, skin eruption, sore throat and bicytopenia. As bone marrow examination revealed an increased proportion of histiocytes and active phagocytosis, hemophagocytic syndrome (HPS) was diagnosed. After admission, the peripheral blood counts recovered spontaneously and the HPS subsided, but other symptoms persisted and the neutrophil count increased. At this time, we diagnosed the patient as having adult Still's disease. All the symptoms disappeared after administration of prednisolone. The markedly increased concentrations of TNF-alpha and IFN-gamma in the peripheral blood at the time of HPS declined gradually, and the IL-6 concentration increased at the time of diagnosis of Still's disease. However, all of these concentrations normalized after administration of prednisolone. As HPS and Still's disease have a common etiology, and each shows high concentrations of IFN-gamma, IL 6 and TNF-alpha, the symptoms are similar in both diseases. In particular, a relationship between HPS and high concentrations of TNF-alpha and IFN-gamma is suspected.
