sdz-psc-833 and Neoplasms

Early publications using cultured cancer cells immediately recognized the phenomenon of resistance to anticancer agents. However, it was not until 1973 that it was first demonstrated that a major factor in the resistance of cancer cells was that of reduced drug accumulation. This year marks the 30th anniversary of the discovery by Juliano and Ling that P-glycoprotein mediates this active efflux of chemotherapeutic drugs from cancer cells. Since this seminal finding, the investigation of P-glycoprotein (MDR1, ATP binding cassette [ABC]B1) has proceeded with great vigour. However, it soon became apparent that P-glycoprotein was not expressed in all drug-resistant cells that displayed an accumulation deficiency, which led to the discovery of other ABC transporters involved in drug efflux. In 1992, the multidrug resistance-associated protein (MRP1, ABCC1) was identified in small cell lung cancer followed by breast cancer resistance protein (mitoxantrone resistance protein, ABCG2) in 1999. After three decades of research, can we confidently define the contribution of multidrug resistance transporters to chemoresistance and do we have clinically useful drugs to sensitise cancers?

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Clinical Trials as Topic; Cyclosporins; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Imidazoles; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Neoplasms; Quinolines; RNA Interference

The last two decades have witnessed dramatic advances into the mechanisms of drug resistance in cancer. The identification of P glycoprotein (Pgp) as a specific mechanism led to the initial hope and expectation that it would be possible to modulate this and increase sensitivity to drug therapy. Clinical trials using first- and second-generation Pgp modulators did establish proof of principle that in some settings, clinical drug resistance could be overcome with the addition of a Pgp modulator-for example, clinical resistance to paclitaxel, a Pgp substrate, in women with ovarian cancer was shown to be overcome in approximately 20% with the addition of PSC 833, a highly effective Pgp modulator. However, evolutionary and adaptive redundancy in resistance mechanisms have tempered clinical results, even with very effective second- and third-generation modulators. The lessons from oncology establish sound methodology for the evaluation of Pgp modulators for safety, tolerability and efficacy in Phase I, II and III clinical trials. This review will focus on some of the early-phase clinical trials with earlier and newer Pgp modulators, either as single agents or in combination with chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clinical Trials as Topic; Cyclosporins; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Humans; Male; Neoplasm Proteins; Neoplasms; Organ Specificity; Ovarian Neoplasms; Paclitaxel

Modulation of P glycoprotein (Pgp) in clinical oncology has had limited success. Contributing factors have included the limitation in our understanding of the tumours in which Pgp overexpression is mechanistically important in clinical drug resistance; the failure to prove that concentrations of modulators achieved in patients were sufficient to inhibit Pgp; and the inability to conclusively prove that Pgp modulation was occurring in tumours in patients. New approaches are needed to determine the clinical settings in which Pgp overexpression plays a major role in resistance. (Clinical trials with third generation modulators are ongoing, including trials with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576. These studies confirm that the concentrations of modulator achieved in patients are able to increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex vivo assay after administration of the antagonist. Finally, a subset of patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged tumours. These results suggest that Pgp modulators can increase drug accumulation in Pgp-expressing tumours and normal tissues in patients. Using third generation Pgp antagonists and properly designed clinical trials, it should be possible to determine the contribution of modulators to the reversal of clinical drug resistance.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzazepines; Clinical Trials as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fluorescent Dyes; Gene Expression Regulation, Neoplastic; Genes, MDR; Humans; Mice; Mice, Knockout; Neoplasm Proteins; Neoplasms; Piperidines; Pyridines; Quinolines; Radionuclide Imaging; Radiopharmaceuticals; Rhodamines; Technetium Tc 99m Sestamibi; Tissue Distribution; Tumor Cells, Cultured

Cellular resistance to a broad spectrum of natural products used as antitumor drugs is believed to be a major cause for the failure of chemotherapy. Flow cytometry has been used for monitoring the expression of drug resistance markers, determining accumulation of fluorescent drugs, and for screening of drugs that enhance chemosensitivity by blocking efflux and enhancing drug retention. This article reviews recent developments in our understanding of the multiple drug resistance phenotype and the use of flow cytometry for the study of drug efflux and its modulation in human tumor cells.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Neoplasms; Neoplastic Stem Cells; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles

Oral treatment with cytotoxic agents is to be preferred as this administration route is convenient to patients, reduces administration costs and facilitates the use of more chronic treatment regimens. For the taxanes paclitaxel and docetaxel, however, low oral bioavailability has limited development of treatment by the oral route. Preclinical studies with mdr1a P-glycoprotein knock-out mice, which lack functional P-glycoprotein activity in the gut, have shown significant bioavailability of orally administered paclitaxel. Additional studies in wild-type mice revealed good bioavailability after oral administration when paclitaxel was combined with P-glycoprotein blockers such as cyclosporin A or the structurally related compound SDZ PSC 833. Based on the extensive preclinical research, the feasibility of oral administration of paclitaxel and docetaxel in cancer patients was recently demonstrated in our Institute. Co-administration of cyclosporin A strongly enhanced the oral bioavailability of both paclitaxel and docetaxel. For docetaxel in combination with cyclosporin A an oral bioavailability of 90% was achieved with an interpatient variability similar to that after intravenous drug administration; for paclitaxel the oral bioavailability is estimated at approximately 50%. The safety of the oral route for both taxanes is good. A phase II study of weekly oral docetaxel in combination with cyclosporin A is currently ongoing.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cyclosporine; Cyclosporins; Docetaxel; Humans; Mice; Mice, Knockout; Neoplasms; Paclitaxel; Taxoids

To review the mechanisms of multidrug resistance (MDR) in human cancer and the clinical use of MDR modulators to overcome or reverse P-glycoprotein (P-gp)-mediated MDR.. Current literature, ongoing clinical trials, and clinical experience.. Agents, such as valspodar, that block the activity of P-gp can reverse or overcome MDR caused by overexpression of P-gp. The MDR modulator valspodar (PSC 833; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is examined as a model for establishing nursing guidelines for this new class of therapeutic agents.. The dose of some chemotherapy agents must be modified with concurrent valspodar administration. Studies examining the safety and efficacy of valspodar as a prototype of MDR modulators provide the basis for establishing nursing care guidelines.. Nursing care for the administration of valspodar includes understanding patient selection, criteria, dosing, and administration; side-effect management; patient monitoring and follow-up; and patient education.

Topics: ATP Binding Cassette Transporter, Subfamily B; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Nursing Care; Oncology Nursing; Patient Education as Topic; Practice Guidelines as Topic

The expression of drug efflux mechanisms by cancer cells during chemotherapy leads to multidrug resistance (MDR) and constitutes a major obstacle in the effective treatment of cancer. The most widely characterized drug effluxes pump is P-glycoprotein (P-gp) and efforts are being directed towards identifying agents that reverse P-gp mediated drug resistance. PSC-833 is a non-immunosuppressive cyclosporin derivative that potently and specifically inhibits P-gp. The current review focuses on the elucidation of the mechanism of action of PSC-833 as a potential MDR reversing agent, using syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cell line that express increasing levels of P-gp. In vitro experiments indicate that PSC-833 interacts directly with P-gp with high affinity and probably interferes with the ATPase activity of P-gp. Studies in multidrug resistant tumor models confirm P-gp as the in vivo target of PSC-833 and demonstrate the ability of PSC-833 to reverse MDR leukemias and solid tumors in mice. Presently, PSC-833 is being evaluated in the clinic.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Mice; Neoplasms; Neoplasms, Experimental; Rats

Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors.. Patients were treated with single-agent paclitaxel Q3W 175 mg/m 2 (or 135 mg/m 2 if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m 2 ), 40% (70 mg/m 2 ), or 50% (87.5 mg/m 2 ) of 175 mg/m 2 (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy.. Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel.. Paclitaxel at 70 mg/m 2 was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; Cyclosporins; Humans; Neoplasms; Paclitaxel

Cellular expression of ATP-binding cassette (ABC) transport proteins, such as P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), or ABCG2, is known to confer a drug-resistant phenotype. Thus, the development of effective transporter inhibitors could be of value to cancer treatment. CBT-1 is a bisbenzylisoquinoline plant alkyloid currently in development as a Pgp inhibitor. We characterized its interactions with the three major ABC transporters associated with drug resistance - Pgp, MRP1 and ABCG2 - and compared it to other known inhibitors. CBT-1 completely inhibited rhodamine 123 transport from Pgp-overexpressing cells at a concentration of 1muM. Additionally, 1 microM completely reversed Pgp-mediated resistance to vinblastine, paclitaxel and depsipeptide in SW620 Ad20 cells. CBT-1 was found to compete [(125)I]-IAAP labeling of Pgp with an IC(50) of 0.14 microM, and low concentrations of CBT-1 (<1 microM) stimulated Pgp-mediated ATP hydrolysis. In MRP1-overexpressing cells, 10 microM CBT-1 was found to completely inhibit MRP1-mediated calcein transport. CBT-1 at 25 microM did not have a significant effect on ABCG2-mediated pheophorbide a transport. Serum levels of CBT-1 in samples obtained from eight patients receiving CBT-1 increased intracellular rhodamine 123 levels in CD56+ cells 2.1- to 5.7-fold in an ex vivo assay. CBT-1 is able to inhibit the ABC transporters Pgp and MRP1, making it an attractive candidate for clinical trials in cancers where Pgp and/or MRP1 might be overexpressed. Further clinical studies with CBT-1 are warranted.

Topics: Adenosine Triphosphatases; Alkaloids; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Biological Factors; Biological Transport; Cell Line; Cell Line, Tumor; Cyclosporins; Depsipeptides; Fluorescent Dyes; Fluorouracil; Humans; Insecta; Multidrug Resistance-Associated Proteins; Neoplasms; Paclitaxel; Prazosin; Quinolines; Rhodamine 123; Verapamil; Vinblastine

The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.. Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.. The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.. The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cyclosporins; Dose-Response Relationship, Drug; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Liposomes; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Paclitaxel

PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion.. Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833.. In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma.. PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; CD56 Antigen; Cyclosporins; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorescent Dyes; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Paclitaxel; Rhodamines; T-Lymphocytes

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations < or = 1000 ng / ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg / kg for both LD and CD with 30 mg / m(2) doxorubicin; these dosages were increased to 2 and 10 mg / kg and 50 mg / m(2), respectively. Thirty-one patients were treated. Nausea / vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-833 > 1000 ng / ml were achieved at a 2 mg / kg LD and a 10 mg / kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC(50) of P-glycoprotein expressing 8226 / Dox(6) in patients' serum was decreased from 5.9 to 1.3 microg / ml (P < 0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 +/- 13.7 (mean +/- SD) liter / h/m(2), which was lower than the 49.0 +/- 16.9 liter / h/m(2) without PSC-833 (P < 0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg / kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg / m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Injections, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Tumor Cells, Cultured

P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel.. For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses.. Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel.. PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Cyclosporins; Doxorubicin; Drug Interactions; Drug Resistance, Multiple; Female; Humans; Male; Middle Aged; Neoplasm Staging; Neoplasms; Paclitaxel; Treatment Outcome

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of paclitaxel when given with PSC 833 (valspodar) to patients with refractory solid tumors.. Patients were initially treated with paclitaxel 175 mg/m(2) continuous intravenous infusion (CIVI) over 3 hours. Subsequently, 29 hours of treatment with CIVI PSC 833 was started 2 hours before paclitaxel treatment was initiated. In this combination, the starting dose of paclitaxel was 52.5 mg/m(2). Paclitaxel doses were escalated by 17.5 mg/m(2) increments for four subsequent cohorts. Each cohort consisted of three patients with the exception of the last cohort, which consisted of six patients. Data for the pharmacokinetics of paclitaxel with and without concurrent PSC 833 administration were obtained.. All 18 patients completed at least one course of concurrent treatment (median, two courses; range, one to six) and were evaluable for toxicity. The MTD for paclitaxel with PSC 833 was 122.5 mg/m(2). Neutropenia was the DLT. All patients had PSC 833 blood concentrations greater than 1, 000 ng/mL before, during, and 24 hours after the paclitaxel infusion. PSC 833 produced small increases in the paclitaxel peak plasma concentrations and areas under the concentration-time curve. However, PSC 833 greatly prolonged the terminal phase of paclitaxel, resulting in plasma paclitaxel concentrations of more than 0.05 micromol/L for much longer than expected. As a result, myelosuppression was comparable to that produced by full-dose paclitaxel given without PSC 833. Of the 16 patients who were assessable for response, one patient experienced a partial response and an additional nine patients experienced disease stabilization after paclitaxel treatment alone.. Treatment with paclitaxel 122.5 mg/m(2) as a 3-hour CIVI concurrent with a 29-hour CIVI of PSC 833 results in acceptable toxicity. The addition of PSC 833 alters the pharmacokinetics of paclitaxel, which explains the enhanced neutropenia experienced by patients treated with this drug combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cyclosporins; Female; Humans; Male; Middle Aged; Neoplasms; Paclitaxel; Treatment Outcome

To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function.. Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1.. Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m(2) and carboplatin AUC 6 mg.min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carboplatin AUC (mg.min/mL) of 67.5/6, 81/6, 94.5/6, 67. 5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/mL.min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was >/= 0.05 micromol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/m(2), respectively.. The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclosporins; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Paclitaxel; Thrombocytopenia

Resistant cancer cells have been shown to overexpress a 170-kd membrane glycoprotein called P-glycoprotein. P-glycoprotein, a product of the multidrug resistance 1 gene, functions as an energy-dependent efflux pump that decreases intracellular drug concentrations. A variety of nonchemotherapeutic agents have been shown to inhibit P-glycoprotein-dependent drug efflux including cyclosporin. PSC 833 is a nonimmunosuppressive derivative of cyclosporin D with the ability to reverse multidrug resistance because of P-glycoprotein overexpression in vitro. As part of early clinical development of PSC 833, the authors investigated the bioavailability of an oral formulation of PSC 833. PSC 833 (3 mg/kg) was administered as a 2-hour intravenous infusion on day 1 of the treatment cycle. Serial blood samples for the determination of PSC 833 whole blood concentrations were obtained after both the intravenous and oral doses. On day 5 of the study, patients received a single oral dose (9 mg/kg) of PSC 833. A total of 14 patients were treated. The intravenous data were best described by a two-compartment open model. The oral data also were described using a two-compartment model, with oral absorption incorporating a lag time to account for possible delays in absorption. There was large intra- and interpatient variability in the pharmacokinetics of PSC 833 in these patients. The absolute bioavailability of PSC 833 was 34% but ranged from 3% to 58% of the administered dose. The clearance (CI) of PSC 833, in general, was consistent between the two dose forms administered. The pharmacokinetic behavior of PSC 833 appears to be similar to that of cyclosporine.

Topics: Administration, Oral; Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cyclosporins; Drug Resistance, Multiple; Female; Half-Life; Humans; Infusions, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Vinblastine

P-glycoprotein (Pgp) is a 170-kDa membrane transporter that mediates drug efflux and is an effector of multidrug resistance. SDZ PSC 833 (PSC), a nonimmunosuppressive cyclosporine that potently modulates Pgp, is currently under clinical evaluation in patients with cancer. We have developed a reversed-phase HPLC assay for determining PSC blood concentrations that utilizes a step gradient with linear segments to resolve PSC into two distinct peaks (likely to be keto and enol isomers). To clinically validate the assay, PSC concentrations were obtained by HPLC from nine patients receiving oral doses of 5 mg/kg every 6 h. Values ranged from 0.91 to 5.4 mg/L during the dosing period, comparable with concentrations of PSC that modulate Pgp in vitro. In addition, we investigated the immunoreactivity of the Abbott TDx cyclosporin A (CsA) monoclonal whole-blood assay for PSC. The TDx CsA assay cross-reacts approximately 17% with PSC as determined by adding known amounts of PSC to whole blood. When PSC concentrations obtained by the TDx CsA assay were divided by 0.17, we found agreement between the TDx CsA assay and the HPLC PSC assay for samples from nine patients.

Topics: Antineoplastic Agents, Phytogenic; Chromatography, High Pressure Liquid; Cross Reactions; Cyclosporine; Cyclosporins; Drug Monitoring; Fluorescence Polarization Immunoassay; Humans; Immunosuppressive Agents; Neoplasms; Paclitaxel; Reproducibility of Results

Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination of doxorubicin with the cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received PSC at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses given every 12 h. Doxorubicin was given by i.v. push on day 3 of PSC administration, 4 h after the morning dose of PSC. Pharmacokinetic analyses of PSC and doxorubicin were performed. A total of 38 patients received a combination of PSC and doxorubicin, and 27 received doxorubicin alone in the first course. The major toxicity of the combination was hematological and was significantly more severe than that with doxorubicin alone; severe myelosuppression was already observed at the first PSC dose level, which required doxorubicin dose reduction from 50 to 35 mg/m2. At all dose levels of PSC, up to 17.5 mg/kg/day, there were at least two patients with grade 3 or 4 hematological toxicity, which was manageable in less heavily pretreated patients. A further PSC dose escalation was performed to 25 mg/kg/day, together with doxorubicin, at a further reduced dose of 20 mg/m2. At this dose, central nervous system toxicity became the most relevant side effect. The increase of toxicity in the combined treatment was supported by a significant increase of the area under the plasma concentration-time curve to infinity of doxorubicin (54%) and a 10-fold increase of the area under the plasma concentration-time curve to infinity of doxorubicinol. The pharmacological interaction was not dependent on the plasma concentration of PSC. The total body clearance of doxorubicin decreased by 30%. PSC plasma concentrations of >1 microM at the time of doxorubicin administration were, in general, found at a dose of 7.5 mg/kg/day or higher. One patient had a partial response. In conclusion, PSC plasma concentrations that can revert multidrug resistance in experimental models could be achieved in patients who have solid tumors and who are treated with doxorubicin. However, a marked pharmacological interaction was found between doxorubicin and PSC, which led to substantial increase in hematological toxicity and required marked reduction of the doxorubicin dose. Further study of PSC may be warranted, in association with the investigation of P-glycoprotein expression and concentration of drugs in the tumor tissues.

Topics: Adult; Aged; Antineoplastic Agents; Cyclosporins; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms

To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics.. Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion).. Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively.. PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Cyclosporins; Drug Resistance, Multiple; Etoposide; Female; Half-Life; Humans; Male; Middle Aged; Neoplasms

ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity.. MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity.. Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters.. A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.

Topics: Aniline Compounds; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Cell Line, Tumor; Cyclosporins; Dasatinib; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Fusion Proteins, bcr-abl; Humans; Indoles; K562 Cells; Neoplasm Proteins; Neoplasms; Nitriles; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Quinolines; Substrate Specificity; Thiazoles

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Cyclosporins; Dibenzocycloheptenes; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs, Investigational; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; National Institutes of Health (U.S.); Neoplasms; Piperidines; Pyridines; Quinolines; United States

Sestamibi, tetrofosmin, and furifosmin are 99mTc-labeled myocardial perfusion imaging agents which have been shown to be substrates for P-glycoprotein (Pgp), the multidrug-resistance transporter which is overexpressed in some tumors. The three tracers were directly compared in vitro in the human breast cancer cell line MCF7-WT and two multidrug-resistant variants, MCF7-BC19 (MDR1 gene transfected) and MCF7-AdrR (doxorubicin selected). Tracer accumulation over the course of 60 minutes was determined. Dose-response curves were generated for two modulators of Pgp function, GG918 and PSC833. The general shape of accumulation curves for the three tracers in MCF7-WT cells was similar, with accumulation levels being sestamibi > tetrofosmin > furifosmin. Accumulation of sestamibi and furifosmin in MCF7-BC19 cells was reduced to 10% and 21% of MCF7-WT levels, respectively, but this accumulation deficit could be completely reversed by addition of 0.1 microM GG918 or 2 microM PSC833. Accumulation of sestamibi and tetrofosmin in MCF7-AdrR cells was 1.6% and 12% of MCF7-WT levels, respectively, and could only be enhanced to 30% and 45% of MCF7-WT levels by addition of GG918 or PSC833. In contrast, furifosmin showed similar levels of accumulation in MCF7-WT and MCF7-BC19 cells, slightly lower levels in MCF7-AdrR cells, and no consistent response to Pgp modulators. These results support the continued investigation of sestamibi and tetrofosmin as agents for functional imaging of multidrug resistance in human cancer.

Topics: Acridines; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Neoplasm; Furans; Humans; Isoquinolines; Neoplasms; Organophosphorus Compounds; Organotechnetium Compounds; Technetium Tc 99m Sestamibi; Tetrahydroisoquinolines; Tomography, Emission-Computed, Single-Photon; Tumor Cells, Cultured

Resistance to chemotherapy is the major cause of cancer treatment failure. Insight into the mechanism of action of agents that modulate multidrug resistance (MDR) is instrumental for the design of more effective treatment modalities. Here we show, using KB-V-1 MDR human epidermoid carcinoma cells and [3H]palmitic acid as metabolic tracer, that the MDR modulator SDZ PSC 833 (PSC 833) activates ceramide synthesis. In a short time course experiment, ceramide was generated as early as 15 min (40% increase) after the addition of PSC 833 (5.0 microM), and by 3 h, [3H]ceramide was >3-fold that of control cells. A 24-h dose-response experiment showed that at 1.0 and 10 microM PSC 833, ceramide levels were 2.5- and 13.6-fold higher, respectively, than in untreated cells. Concomitant with the increase in cellular ceramide was a progressive decrease in cell survival, suggesting that ceramide elicited a cytotoxic response. Analysis of DNA in cells treated with PSC 833 showed oligonucleosomal DNA fragmentation, characteristic of apoptosis. The inclusion of fumonisin B1, a ceramide synthase inhibitor, blocked PSC 833-induced ceramide generation. Assessment of ceramide mass by TLC lipid charring confirmed that PSC 833 markedly enhanced ceramide synthesis, not only in KB-V-1 cells but also in wild-type KB-3-1 cells. The capacity of PSC 833 to reverse drug resistance was demonstrated with vinblastine. Whereas each agent at a concentration of 1.0 microM reduced cell survival by approximately 20%, when PSC 833 and vinblastine were coadministered, cell viability fell to zero. In parallel experiments measuring ceramide metabolism, it was shown that the PSC 833/vinblastine combination synergistically increased cellular ceramide levels. Vinblastine toxicity, also intensified by PSC 833 in wild-type KB-3-1 cells, was as well accompanied by enhanced ceramide formation. These data demonstrate that PSC 833 has mechanisms of action in addition to P-glycoprotein chemotherapy efflux pumping.

Topics: Cell Survival; Ceramides; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; KB Cells; Neoplasms; Palmitic Acid; Vinblastine

Resistance of cancer cells is the major limitation to the success of chemotherapy. Although many mechanisms of cellular resistance to anticancer drugs have been defined, the best understood of these is multidrug resistance (MDR), caused by the multidrug transporter, P-glycoprotein (P-gp), the product of the MDR1 gene. New drugs developed specifically to inhibit P-gp and modulate MDR, such as valspodar (PSC 833 [Amdray]), are currently undergoing clinical testing. Moreover, agents designed to inhibit other mechanisms of drug resistance are currently in development, and concurrent blockade of multiple mechanisms of resistance appears to be a promising approach. Coadministration of MDR1-related chemotherapeutic drugs with an MDR modulator may enhance the bioavailability of these agents sufficiently to enable oral dosing, which would potentially be more convenient and less toxic.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clinical Trials as Topic; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms

Topics: Animals; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Neoplasms; Neoplasms, Experimental; Sarcoma, Experimental; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Clinical Trials, Phase I as Topic; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Male; Neoplasms; Paclitaxel