sdz-psc-833 and Carcinoma

To determine the maximum-tolerated dose (MTD) of doxorubicin when given in combination with cisplatin and the multidrug-resistance (MDR) modulator valspodar and the remission rate induced by this combination in patients with platinum- and anthracycline-resistant ovarian cancer.. Fifty-nine patients who had failed prior platinum- and anthracycline-based chemotherapy were enrolled. During the dose-finding phase, patients received a loading dose of valspodar (1.5 or 2 mg/kg) via 2-hour intravenous (IV) infusion on day 1 and continuous IV infusion (CIVI) of valspodar (2, 4, or 10 mg/kg/d) over 3 days. Doxorubicin (starting from 20 up to 50 mg/m(2)) and cisplatin (50 mg/m(2)) were administered via 15- to 20-minute IV infusions on day 3. During the efficacy phase, patients received at least two treatment cycles unless toxicity was unacceptable, and responding patients and those with stable disease received four to six cycles.. All patients completed at least one cycle of combined treatment. The MTD of doxorubicin was determined to be 35 mg/m(2) when administered with valspodar at 2 mg/kg loading dose and 10 mg/kg/d CIVI plus 50 mg/m(2) cisplatin. At these doses, valspodar blood concentrations known to reverse MDR in vitro were reached in all patients. Valspodar was well tolerated at all dose levels. Dose-limiting toxicities of the combination were primarily hematologic and included febrile neutropenia and prolonged leucopenia. The addition of valspodar to the treatment did not worsen cisplatin-related toxicity. Among 33 patients treated at the MTD for doxorubicin, one (3%) had a complete response, and four (12%) had a partial response. An additional seven patients experienced a stabilization of their previously progressive disease. The survival rates at 6 and 12 months were 59% and 19%, respectively.. Valspodar can be safely coadministered with doxorubicin and cisplatin. Although the regimen used in this trial produced renewed responses in patients with heavily pretreated, refractory ovarian cancer, the value of valspodar in reversing resistance mediated by P-glycoprotein remains to be determined.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Maximum Tolerated Dose; Middle Aged; Ovarian Neoplasms; Salvage Therapy; Survival Rate

A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer.. Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein.. Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients.. Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma; Cyclosporins; Disease-Free Survival; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Paclitaxel; Survival Rate

We have previously demonstrated that liposome encapsulation of doxorubicin (DOX) can alleviate adverse interactions with non-encapsulated DOX and the cyclosporine multidrug-resistant (MDR) modulator Valspodar. We have now investigated the behavior of different liposomal DOX formulations in MDA435LCC6/MDR-1 human breast cancer solid tumor xenograft models to identify liposome characteristics associated with enhanced therapeutic activity and the mechanism whereby increased chemosensitization is achieved. Toxicity studies incorporating conventional phosphatidylcholine (PC)/cholesterol (chol) and sterically stabilized (polyethylene glycol 2000 [PEG]-containing) formulations of DOX indicated that whereas PC/Chol DOX was approximately 3-fold more toxic in the presence of Valspodar, PEG containing distearoylglycerophosphocholine (DSPC)/Chol DOX was minimally affected. In mice bearing MDR tumors, co-administration of Valspodar and egg phosphocholine (EPC)/Chol DOX resulted in modest MDR modulation and efficacy, whereas the sterically stabilized formulation induced reductions in tumor growth equivalent to that achieved for drug-sensitive tumors treated with non-encapsulated DOX. Pharmacokinetic studies revealed a 2.5-fold increase in plasma DOX area under the curve (AUC) upon co-administration of Valspodar with EPC/Chol DOX whereas no such alterations were observed with the sterically stabilized liposomes. Compared to non-encapsulated DOX combined with Valspodar, improvements in efficacy and toxicity correlated with the extent to which liposomal DOX formulations were able to circumvent pharmacokinetic interactions. Confocal microscopy demonstrated that Valspodar increased cell-associated DOX which correlated with the level of anti-tumor efficacy.

Topics: Animals; Carcinoma; Cell Division; Cyclosporins; Dose-Response Relationship, Drug; Doxorubicin; Drug Carriers; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Intracellular Fluid; Liposomes; Mammary Neoplasms, Experimental; Mice; Mice, SCID; Neoplasm Transplantation; Tissue Distribution; Tumor Cells, Cultured

The present study examines whether resistance to Cyclosporin A (CyA) and Tacrolimus (FK506) develops in T cells from individual patients and the role of P-glycoprotein 170 (P-gp) in mediating drug resistance. IC50s were established for CyA and FK506 in cell cultures from 46 renal allograft recipients. P-gp expression and functional activity were determined by flow cytometry. Mean ID50 for CyA was 29 microg/li (range 2.5-100) and for FK506 1.2 microg/li (range 0.085-5.5). The sensitivities to the two drugs were correlated (P = 0.0001). There was variation in the ratio of the ID50s depending on the drug used for treatment (P = 0.02). There was no difference in P-gp expression and functional activity in patients with sensitive or resistant cells. The data indicate an association between the sensitivities to CyA and FK506 and evidence of selective resistance to whichever drug was used. P-gp drug transport does not explain this variation.

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Calcineurin; Calcineurin Inhibitors; Carcinoma; Cells, Cultured; Cyclosporine; Cyclosporins; Drug Resistance; Drug Tolerance; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; T-Lymphocytes; Tacrolimus; Tumor Cells, Cultured

Topics: Carcinoma; Cell Survival; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms; Paclitaxel; Radiation-Sensitizing Agents; Tumor Cells, Cultured