Epithelial ovarian cancer (OC) is a common gynecologic malignancy in women. The standard treatment for OC is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. Despite the high response rate to primary therapy, approximately 85% of patients will develop recurrent ovarian cancer (ROC). This review identifies the clinical use of trabectedin in the treatment algorithm for ROC, with specific emphasis on platinum-sensitive ROC, for which trabectedin in combination with pegylated liposomal doxorubicin has been approved as a treatment protocol. The main mechanisms of action of trabectedin at the cellular level and in the tumor microenvironment is also discussed as bases for identifying biomarkers for selecting patients who may largely benefit from trabectedin-based therapies.
Antineoplastic Agents, Alkylating ; therapeutic use ; Clinical Trials as Topic ; DNA Damage ; Dioxoles ; administration & dosage ; pharmacology ; therapeutic use ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Female ; Humans ; Neoplasm Recurrence, Local ; drug therapy ; Neoplasms, Glandular and Epithelial ; drug therapy ; Ovarian Neoplasms ; drug therapy ; Polyethylene Glycols ; administration & dosage ; Tetrahydroisoquinolines ; administration & dosage ; pharmacology ; therapeutic use ; Tumor Microenvironment

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) act by irreversibly binding to the H+-K+-ATPase of the proton pump in parietal cells and may possibly affect the vacuolar H+-ATPase in osteoclasts. METHODS: We investigated the effect of 8 weeks of PPI treatment on the parameters of bone turnover and compared PPI with revaprazan, which acts by reversibly binding to H+-K+-ATPase in proton pumps. This study was a parallel randomized controlled trial. For 8 weeks, either a PPI or revaprazan was randomly assigned to patients with gastric ulcers. The parameters of bone turnover were measured at the beginning of and after the 8-week treatment period. RESULTS: Twenty-six patients (PPI, n=13; revaprazan, n=13) completed the intention-to-treat analysis. After the 8-week treatment period, serum calcium and urine deoxypyridinoline (DPD) were increased in the PPI group (serum calcium, p=0.046; urine DPD, p=0.046) but not in the revaprazan group. According to multivariate linear regression analysis, age > or =60 years was an independent predictor for the changes in serum calcium and urine DPD. CONCLUSIONS: In elderly patients, administering a PPI for 8 weeks altered bone parameters. Our study suggested that PPIs might directly alter bone metabolism via the vacuolar H+-ATPase in osteoclasts.
Aged ; Amino Acids/drug effects/urine ; Bone Remodeling/*drug effects ; Bone and Bones/*metabolism ; Calcium/blood ; Female ; Humans ; Intention to Treat Analysis ; Linear Models ; Male ; Middle Aged ; Multivariate Analysis ; Osteoclasts/*metabolism ; Prospective Studies ; Proton Pump Inhibitors/*pharmacology ; Pyrimidinones/*pharmacology ; Tetrahydroisoquinolines/*pharmacology

To establish a pig kidney cell line LLC-PK1/BCRP in which human breast cancer resistance protein was highly expressed, the expression vector pcDNA3.1(+)-BCRP which contained BCRP gene was constructed and transfected into LLC-PKI cells via liposomes. After selecting with G418, population doubling time, flow cytometry and Western blotting analysis were used to evaluate the cell line. MTT assays were employed to determine the drug resistance index of mitoxantrone and doxorubicin. Invert fluorescent microscope was used to observe the efflux of fluorescence dye Hoechst 33342 by BCRP, furthermore, the BCRP's inhibitor GF120918 was applied to reverse the efflux of Hoechst 33342. The experiment results showed that the expression of BCRP protein increased in LLC-PK1/BCRP cell. The population doubling time of LLC-PK1/BCRP cell was a little longer than that of the parental cell LLC-PK1. The resistance indexes to mitoxantrone and doxorubicin were 51.95 and 6.09 times, respectively, higher than LLC-PK1 cell. The efflux of Hoechst 33342 was significantly enhanced and could be reversed by GF120918. So a LLC-PK1/BCRP cell line was established, which highly expressed BCRP protein successfully. This cell line could be a valuable model to further investigate the biological profile of BCRP and select the substrate and inhibitor of BCRP.
ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; genetics ; metabolism ; Acridines ; pharmacology ; Animals ; Benzimidazoles ; metabolism ; Cell Cycle ; Cell Proliferation ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; Genetic Vectors ; LLC-PK1 Cells ; cytology ; metabolism ; Mitoxantrone ; pharmacology ; Neoplasm Proteins ; genetics ; metabolism ; Plasmids ; Swine ; Tetrahydroisoquinolines ; pharmacology ; Transfection

A series of tetrahydroisoquinoline derivatives were prepared and their peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonistic activities were evaluated to obtain more potent PPAR agonist. All of them were new compounds, and their structures were confirmed by 1H NMR and HR-MS. Three compounds exhibited higher agonistic activities of PPARgamma than that of the comparison, six compounds exhibited higher agonistic activities of PPARalpha than that of the comparison, and compound 8a was discovered as a highly potent PPARalpha/gamma agonist that is much more active than that of WY14643 and rosiglitazone. The development of potent PPAR agonists may offer a new choice for the treatment of diabetes.
Drug Design ; HEK293 Cells ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; PPAR alpha ; agonists ; metabolism ; PPAR gamma ; agonists ; metabolism ; Structure-Activity Relationship ; Tetrahydroisoquinolines ; chemical synthesis ; chemistry ; pharmacology ; Transfection

Tetrahydroisoquinoline alkaloids distributed widely in the nature and some have a broad application in clinic. More attention has been paid in recent years on this type of alkaloid, owing to the diverse range of biological activities exhibited by these alkaloids and the discovery of new functional mechanisms and molecular targets underlying these activities. This article summarized the recent advances in the biological activities and functional mechanism of tetrahydroisoquinoline, which included the activities such as antitumor, antibiotic, antivirus, anti-inflammatory, anticoagulation, bronchodilation, and the action on central nervous system, with the purpose of providing some ideas in the study of biological activity of this type of alkaloid and in the search for lead-compound and rational drug design.
Animals ; Anti-Inflammatory Agents ; pharmacology ; Anticonvulsants ; pharmacology ; Antifungal Agents ; pharmacology ; Antineoplastic Agents ; pharmacology ; Antiviral Agents ; pharmacology ; Bronchodilator Agents ; pharmacology ; Central Nervous System Agents ; pharmacology ; Fibrinolytic Agents ; pharmacology ; Humans ; Neuroprotective Agents ; pharmacology ; Tetrahydroisoquinolines ; chemical synthesis ; chemistry ; pharmacology

Gastrodin (GAS) is the major bioactive component of the extracts from the rhizome of Gastrodia elata Blume. The aim of this study is to investigate the transport of GAS in Caco-2 cells and the interaction of P-glycoprotein and GAS. The apparent permeability coefficients (Papp) of GAS were measured as a function of directions and concentrations. It was demonstrated that the efflux ratio was < 2.0 over the range of 50-500 micromol x L(-1) of GAS from bi-directional transport studies. The transport rate of GAS was dependent on the concentrations. Papp of GAS was not affected by transport directions, GAS concentration or the classical inhibitors of P-glycoprotein (verapamil and GF 120918). The cellular accumulation of GAS in Bcap37/MDR1 cells transected with hMDR1 gene, was similar to that in Bcap37 cells. The accumulation in both cell lines was concentration dependent. GAS did not affect the accumulation of Rhodamine 123 in Bcap37/MDR1 cells over the range of 50-500 micromol x L(-1). It indicated that the transport of GAS in Caco-2 cell monolayers mainly is by passive paracellular transport pathway. P-glycoprotein did not participate in the absorption of GAS in the intestine or the transport across the blood-brain barrier.
ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; metabolism ; Acridines ; pharmacology ; Benzyl Alcohols ; isolation & purification ; pharmacokinetics ; Biological Transport ; Blood-Brain Barrier ; Breast Neoplasms ; pathology ; Caco-2 Cells ; Cell Line, Tumor ; Drug Resistance, Multiple ; Gastrodia ; chemistry ; Glucosides ; isolation & purification ; pharmacokinetics ; Humans ; Plants, Medicinal ; chemistry ; Rhodamine 123 ; pharmacokinetics ; Tetrahydroisoquinolines ; pharmacology ; Verapamil ; pharmacology

OBJECTIVETo investigate the effect of dauricine on the apoptosis of neuronal cells and the expression of apoptosis-related proteins in the brain penumbra of rats induced by transient focal cerebral ischemia-reperfusion injury.

METHODMale SD rats were randomly divided into five groups: sham group (Sham), model group (Model), and Dauricine groups of low, middle and high doses. To make the transient focal cerebral ischemia-reperfusion injury model, the middle cerebral artery on the right side of rat was occluded by inserting a nylon suture through the internal carotid artery for 1 h, followed by reperfusion for 24 h after withdrawing the suture. Dauricine groups, different doses of Dauricine (2.5, 5, 10 mg x kg(-1) as low, middle and high dose respectively) were administered intraperitoneally at the beginning of the cerebral ischemia, and at 11 h and 23 h after reperfusion. At the same time, Sham group and Model group was administered saline as controls. Brain samples of rats were treated with paraformaldehyde perfusion fixation 24 h after blood reperfusion and then collected for making pathological sections. Apoptotic changes of neuronal cells in the brain penumbra of rat were evaluated in situ by terminal deoxyribonucleotidyl transferasemediated dUTP-digoxigenin nick end-labelling (TUNEL). Cytochrome C (Cyt-C) release and the expression of caspase -3 and caspase -9 proteins of the ischemic-reperfusion brain tissue were determined by immunohistochemistry assay.

RESULTTUNEL-positive cells in groups of middle and high doses of dauricine (18.9 +/- 2.02 and 15.9 +/- 2.9 cells/mm2 respectively) decreased significantly compared with model group (25.5 +/- 3.3 cells/mm2, P<0.05). Cyt-C release and the expression of caspase-3 and caspase-9 proteins in groups of middle and high doses of dauricine were also inhibited compared with Model group (P<0.01).

CONCLUSIONThe mechanism of the neuroprotective effect of dauricine after cerebral ischemia-reperfusion injury may parly, related with an inhibition of neuronal cells apoptosis in the penumbra.

Animals ; Apoptosis ; drug effects ; Benzylisoquinolines ; pharmacology ; Caspases ; metabolism ; Cytochromes c ; metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation ; drug effects ; Ischemic Attack, Transient ; surgery ; Male ; Neuroprotective Agents ; pharmacology ; Rats ; Reperfusion Injury ; metabolism ; pathology ; prevention & control ; Tetrahydroisoquinolines ; pharmacology

Marine antitumor drugs have been the research focus in the world. Recently, advancement has been made in the investigation of six types of compounds including bryostatin-1, ecteinascidin-743, dolastatin, didemnin B, psammaplin and halichondrin B. In this review, we summarized the recent research progress of the above mentioned marine antitumor drugs and their derivatives. Also, the development tendency of marine antitumor drugs was discussed.
Animals ; Antineoplastic Agents ; pharmacology ; therapeutic use ; Apoptosis ; drug effects ; Biological Products ; isolation & purification ; pharmacology ; therapeutic use ; Bryostatins ; isolation & purification ; pharmacology ; therapeutic use ; Cell Line, Tumor ; drug effects ; Depsipeptides ; isolation & purification ; pharmacology ; therapeutic use ; Dioxoles ; isolation & purification ; pharmacology ; therapeutic use ; Disulfides ; isolation & purification ; pharmacology ; Ethers, Cyclic ; isolation & purification ; pharmacology ; Humans ; Macrolides ; Marine Biology ; Neoplasms ; drug therapy ; pathology ; Tetrahydroisoquinolines ; isolation & purification ; pharmacology ; therapeutic use ; Tyrosine ; analogs & derivatives ; isolation & purification ; pharmacology

Alkaloids ; pharmacology ; Animals ; Calcium ; metabolism ; Creatine Kinase ; blood ; Creatine Kinase, MB Form ; Drugs, Chinese Herbal ; pharmacology ; Female ; Ginsenosides ; pharmacology ; Injections ; Isoenzymes ; blood ; Male ; Malondialdehyde ; analysis ; Mitochondria, Heart ; drug effects ; pathology ; Myocardial Reperfusion Injury ; drug therapy ; pathology ; Myocardium ; ultrastructure ; Protective Agents ; pharmacology ; Rabbits ; Tetrahydroisoquinolines ; pharmacology

AIMTo get some novel potent compounds with NOS inhibitory activity, a series of new compounds of isothioureas derived from 1,2,3,4-tetrahydroisoquinoline were synthesized.

METHODS1,2, 3,4-Tetrahydroisoquinol-2-yl was introduced into the structure of isothioureas, the NOS inhibitory activity of the new compounds synthesized were measured.

RESULTS AND CONCLUSIONTwenty-two isothiourea derivatives of [alkyl(or aryl) imino] (1,2,3,4-tetrahydroisoquinol-2-yl) methyl alkyl thioethers (I) and S-alkyl-1-phenyl-3-[4-(1,2,3,4-tetrahydroisoquinol-2-yl) methane] phenyl isothioureas (II) were synthesized from thioureas by S-alkylation with alkyl halides, and their structures were identified by IR, 1H NMR, MS and elemental analysis. The preliminary biological test showed that the part of type I (1-9 and 1-13) had higher NOS inhibitory activity than that the control aminoguanidine (AG), but the type II had weak ability to inhibit NOS.

Molecular Structure ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Stereoisomerism ; Tetrahydroisoquinolines ; chemistry ; Thiourea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology