sdz-psc-833 and Acute-Disease

P-glycoprotein (Pgp) expression is an independent prognostic factor for response to remission-induction chemotherapy in acute myeloblastic leukaemia, particularly in the elderly. There are several potential agents for modulating Pgp-mediated multi-drug resistance, such as cyclosporin A and PSC833, which are currently being evaluated in clinical trials. An alternative therapeutic strategy is to increase the use of drugs which are unaffected by Pgp. However, in this review, we explain why this may be more difficult than it appears. Evidence from in vitro studies of primary AML blasts supports the commonly held supposition that chemoresistance may be linked to apoptosis-resistance. We have found that Pgp has a drug-independent role in the inhibition of in vitro apoptosis in AML blasts. Modulation of cytokine efflux, signalling lipids and intracellular pH have all been suggested as ways by which Pgp may affect cellular resistance to apoptosis; these are discussed in this review. For a chemosensitising agent to be successful, it may be more important for it to enhance apoptosis than to increase drug uptake.

Topics: Acute Disease; Adult; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Division; Ceramides; Child; Cyclosporine; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Hydrogen-Ion Concentration; Leukemia, Myeloid; Lovastatin; Multicenter Studies as Topic; Neoplasm Proteins; Oxides; Phenotype; Protein Kinase C; Randomized Controlled Trials as Topic; Signal Transduction; Tumor Cells, Cultured

Resistance to natural product-derived anti-cancer drugs, such as the anthracyclines and etoposide, contributes to the failure of chemotherapeutic treatment of leukaemia. One biological resistance mechanism of potential importance is the overexpression of the plasma membrane drug transporter proteins P-glycoprotein (Pgp) and multidrug resistance protein (MRP). Many studies have reported evidence for a correlation of Pgp/MDR1 expression with unfavourable prognostic features in acute myeloid leukaemia (AML). Failure to achieve complete remission (CR) is correlated with Pgp and the CD34+ phenotype. For MRP fewer data are available, which suggest a basal expression level in most AMLs. Another protein reported to correlate with treatment failure in AML is the lung resistance protein or major vault protein (LRP), a protein with a still unknown function. Co-expression of Pgp and LRP especially seems to define an adverse prognostic population. Further progress towards the understanding of the clinical importance of these proteins is hampered by the lack of validation of methods to determine their expression. A reliable way to measure Pgp seems to be the assessment of the active transport of fluorescent Pgp substrates, such as rhodamine 123 out of AML cells. Such functional Pgp assays can be used to validate mRNA or protein measurements and to quantify the effect of Pgp or the magnitude of the effect of a blocker of the Pgp-mediated drug efflux on the intracellular drug concentration. The prognostic value of such methods has still to be shown.

Topics: Acute Disease; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Cyclosporins; Drug Resistance, Multiple; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Prognosis; Ribonucleoproteins; Vault Ribonucleoprotein Particles

P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.. A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.. Doses selected for phase III testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients < or = 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.. A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients < or = 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Cytarabine; Daunorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Leukemia, Myeloid; Logistic Models; Male; Middle Aged; Survival Analysis; Treatment Outcome

The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate.Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10 mg/kg per 24 h in combination with daunorubicin 45 mg/m(2) for 3 days and cytarabine 1 g/m(2) twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cause of Death; Cyclosporins; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Humans; Leukemia, Myeloid; Middle Aged; Remission Induction; Salvage Therapy; Treatment Outcome

The purpose of the study is to investigate the tolerability of interleukin 2 (IL-2) after intensive chemotherapy in elderly acute myeloid leukemia (AML) patients in first complete remission (CR).. AML patients > or =60 years in CR after induction and consolidation chemotherapy on Cancer and Leukemia Group B study 9420 were eligible if they had neutrophils > or =1 x 10(9)/liters and platelets > or =75 x 10(9)/liters. Patients received low-dose IL-2 (1 x 10(6) IU/m(2)/day s.c. for 90 days) or low-dose IL-2 with intermediate pulse doses (6-12 x 10(6) IU/m(2)/day s.c. for 3 days) every 14 days (maximum five pulses). In a subset of patients, we investigated the expression of NKG2D ligands by leukemic cells because they are likely important mediators of natural killer cytotoxicity.. Of 35 CR patients receiving IL-2, 34 were evaluable for toxicity. Median age was 67 (range, 60-76) years. Thirteen of 16 patients receiving low-dose IL-2 completed the planned therapy, and 11 of 18 who also received intermediate pulse dose IL-2 therapy completed all five pulses. The spectrum of toxicity in both groups was similar, with predominantly grade 1-2 fatigue, fever, injection site reactions, nausea, anemia, and thrombocytopenia. Grade 3-4 hematological and nonhematological toxicity were more frequent in patients also receiving intermediate pulse dose IL-2 therapy. Grade 3-4 fatigue and hematological toxicity, although uncommon, were the major causes for discontinuing or attenuating therapy. In 8 cases, mRNA for one or more NKG2D ligands was detected in leukemic cells obtained at diagnosis before treatment.. Low-dose IL-2, with or without intermediate pulse dose therapy, given immediately after chemotherapy in first CR to elderly AML patients is well tolerated. Expression of NKG2D ligands by leukemic cells was detected in the majority of cases tested and should be assessed for correlation with response to IL-2 in future studies.

Topics: Acute Disease; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclosporins; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Etoposide; Fatigue; Gene Expression Regulation, Neoplastic; Hematologic Diseases; Humans; Immunologic Factors; Interleukin-2; Killer Cells, Natural; Leukemia, Myeloid; Life Tables; Middle Aged; Nausea; Neoplasm Proteins; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Immunologic; Receptors, Natural Killer Cell; Recombinant Fusion Proteins; Remission Induction; Survival Analysis; Treatment Outcome

To determine the maximum-tolerated dose, pharmacokinetic interaction, and activity of PSC 833 compared with daunorubicin (DNR) and cytarabine in patients with poor-risk acute myeloid leukemia.. Patients received ara-C 3 g/m(2)/d on 5 consecutive days, followed by an IV loading dose of PSC 833 (1.5 mg/kg) and an 84-hour continuous infusion escalating from 6, 9, or 10 mg/kg/d. Daunorubicin was administered as a 72-hour continuous infusion at 34 or 45 mg/m2/d [corrected]. Responding patients received consolidation chemotherapy with DNR pharmacokinetics performed without PSC-833 on day 1, and with PSC-833 on day 4. Response was correlated with expression of P-glycoprotein and lung resistance protein (LRP), and in vitro sensitization of leukemia progenitors to DNR cytotoxicity by PSC 833.. All 43 patients are assessable for toxicity and response. Grade 3 or greater hyperbilirubinemia (70%) was the only dose-dependent toxicity. Four patients (9%) succumbed to treatment-related complications. Twenty-one patients (49%) achieved a complete remission or restored chronic phase, including 10 of 20 patients treated at the maximum-tolerated dose of 10 mg/kg/d of PSC-833 and 45 mg/m(2) of DNR. The 95% confidence interval for complete response was 33.9% to 63.7%. Administration of PSC 833 did not alter the mean area under the curve for DNR, although clearance decreased approximately two-fold (P =.04). Daunorubicinol clearance decreased 3.3-fold (P =.016). Remission rates were not effected by mdr-1 expression, but LRP overexpression was associated with chemotherapy resistance.. Combined treatment with infused PSC 833 and DNR is well tolerated and has activity in patients with poor risk acute myeloid leukemia. Administration of PSC 833 delays elimination of daunorubicinol, but yields variable changes in DNR systemic exposure.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Cyclosporins; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Infusions, Intravenous; Leukemia, Myeloid; Male; Middle Aged; Risk Factors; Treatment Outcome

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Disease-Free Survival; Etoposide; Female; Humans; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Survival Analysis; Treatment Outcome

This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy.. Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR.. Valspodar was well tolerated at the lower DNR dose level (ie, 35 mg/m(2)) resulting in a 21% rate of DLT and only three toxic deaths. Treatment-related mortality was unacceptably high at the 45 mg/m(2) DNR dose level. The complete response rate was 49% overall and similar in both cohorts. The median overall survival of patients was 333 days in cohort 1 compared to 98 days in cohort 2. At baseline, 70% of assessable patients were P-glycoprotein positive.. Substantial inhibition of P-glycoprotein activity can be achieved in this patient population at clinically tolerable doses of valspodar and DNR. The maximum tolerated dose of DNR was established as 35 mg/m(2). This regimen is being further evaluated in phase III trials.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cohort Studies; Cyclosporins; Cytarabine; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Edema; Female; Fever; Humans; Hypokalemia; Leukemia, Myeloid; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neoplasm Proteins; Remission Induction; Survival Analysis; Survival Rate; Treatment Outcome

The Cancer and Leukemia Group B conducted parallel phase I trials of cytarabine, daunorubicin, and etoposide (ADE) with or without PSC-833 (P), a modulator of p-glycoprotein-mediated multidrug resistance.. One hundred ten newly diagnosed patients > or = 60 years of age with de novo acute myeloid leukemia (AML) were treated. All patients received cytarabine by continuous infusion for 7 days at 100 mg/m(2)/d. The starting dose of daunorubicin was 30 mg/m(2)/d for 3 days. Etoposide was administered at a dose of 100 mg/m(2)/d for 3 days, except in the last cohort administered ADEP, who received 60 mg/m(2). PSC-833 was given intravenously with a loading dose of 1.5 mg/kg over 2 hours and a simultaneous continuous infusion of 10 mg/kg/d continued until 24 hours after the last dose of daunorubicin or etoposide.. There was no toxicity attributed to the PSC-833. Dose-limiting toxicity was primarily gastrointestinal (diarrhea, mucositis in the ADEP group). The estimated maximum-tolerated doses, calculated using a logistic regression model, were daunorubicin 40 mg/m(2)/d for 3 days with etoposide 60 mg/m(2) for 3 days in the ADEP group and daunorubicin 60 mg/m(2)/d for 3 days and etoposide 100 mg/m(2)/d for 3 days in the ADE group. Twenty-one (48%) of 44 patients achieved complete remission with ADE, compared with 29 (44%) of 66 patients treated with ADEP.. It is necessary to decrease the doses of daunorubicin and etoposide when they are administered with PSC-833, presumably because of the effect of the modulator on the pharmacokinetics of these agents. A phase III trial comparing the regimens derived from this phase I trial has recently begun.

Topics: Acute Disease; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclosporins; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Leukemia, Myeloid; Male; Middle Aged

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed prognostic classifications with distinct discrepancies. To further study the prognostic value of cytogenetic abnormalities in this patient population, we have evaluated cytogenetic abnormalities in a series of 293 untreated patients with AML aged 60 years and older, included in a randomised phase 3 trial, also in relation to patient characteristics and clinical outcome. The most frequently observed cytogenetic abnormality was trisomy 8 (+8), in 31 (11%) patients. Abnormalities, such as -5, 5q-, abn(17p) and abn(17q), were almost exclusively present in complex karyotypes. A relatively favourable outcome was only observed in five patients with core-binding factor abnormalities t(8;21) and inv(16)/del(16)/t(16;16). However, most of the other evaluated cytogenetic abnormalities, such as 5q-, -7, +8, abn(17p), abn(17q), and complex aberrations expressed a more adverse prognosis when compared with patients with AML aged 60 years and older with a normal karyotype. Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chromosome Aberrations; Cyclosporins; Disease-Free Survival; Female; Genes, MDR; Humans; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome

The ability of acute myeloid leukaemia (AML) blasts to survive in culture has been associated with poor patient response to chemotherapy. Other biological factors predicting an adverse outcome include p-glycoprotein (pgp) expression, which is associated with a reduced remission rate, and the presence of fms-like tyrosine kinase 3 gene (FLT3) internal tandem duplications (ITDs), predictive of a high rate of leukaemic relapse. Our previous work has indicated a drug efflux-independent role for pgp in apoptosis resistance. We measured spontaneous in vitro apoptosis in 58 primary AML samples to establish its relationship with functional and phenotypic pgp and with FLT3 ITDs. Cells were incubated for 48 h in a suspension culture, and the remaining viable cells were counted by flow cytometry. Median survival was 38% of baseline values. Resistance to spontaneous apoptosis was strongly associated with pgp (MRK-16 antibody) expression (P = 0.001) and with pgp functional activity (P < 0.001). FLT3 ITDs, found in 20 cases, were inversely associated with functional pgp activity: thus, the median pgp modulation ratio was 2.0 in FLT3 wild-type cases and 1.38 in ITD cases (P = 0.018). Also, the presence of FLT3 ITDs was not associated with in vitro apoptosis resistance. In conclusion, we have found that the presence of FLT3 ITDs is not related to AML blast survival in vitro, and is inversely associated with pgp activity, whereas pgp expression and activity are associated with resistance to spontaneous apoptosis. These results may help to explain the differing adverse effects of pgp (on remission induction) and FLT3 ITDs (on relapse) in AML.

Topics: Acute Disease; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Multiple; Flow Cytometry; Fluorescent Dyes; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Remission Induction; Repetitive Sequences, Nucleic Acid; Rhodamine 123; Statistics, Nonparametric; Tumor Cells, Cultured

Gemtuzumab ozogamicin (CMA-676), a calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, has recently been introduced clinically as a promising drug for the treatment of patients with acute myeloid leukemia (AML), more than 90% of which express CD33 antigen. However, our recent study suggested that CMA-676 was excreted by a multi- drug-resistance (MDR) mechanism in P-glycoprotein (P-gp)-expressing leukemia cell lines. We analyzed the in vitro effects of CMA-676 on leukemia cells from 27 AML patients in relation to the amount of P-gp, MDR-associated protein 1 (MRP1), CD33 and CD34, using a multi-laser-equipped flow cytometer. The cytocidal effect of CMA-676, estimated by the amount of hypodiploid portion on cell cycle, was inversely related to the amount of P-gp estimated by MRK16 monoclonal antibody (P = 0.004), and to the P-gp function assessed by intracellular rhodamine-123 accumulation in the presence of PSC833 or MS209 as a MDR modifier (P = 0.0004 and P = 0.002, respectively). In addition, these MDR modifiers reversed CMA-676 resistance in P-gp-expressing CD33(+) leukemia cells (P = 0.001 with PSC833 and P = 0.0007 with MS209). In CD33(+) AML cells from 13 patients, CMA-676 was less effective on CD33(+)CD34(+) than CD33(+)CD34(-) cells (P = 0.002). PSC833 partially restored the effect of CMA-676 in CD33(+)CD34(+) cells. These results suggest that the combined use of CMA-676 and a MDR modifier will be more effective on CD33(+) AML with P-gp-related MDR.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, CD34; Antigens, Differentiation, Myelomonocytic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cyclosporins; Drug Interactions; Drug Resistance, Neoplasm; Female; Gemtuzumab; Humans; Immunotoxins; Leukemia, Myeloid; Male; Middle Aged; Quinolines; Sialic Acid Binding Ig-like Lectin 3; Tumor Cells, Cultured

The multidrug resistance (MDR) modulating activity of SDZ-PSC833 (PSC), a non-immunosuppressive cyclosporine analogue, was investigated and compared with cyclosporin A (CSA) in bone marrow clinical specimens from 45 patients with acute myeloid leukaemia (AML) taken at diagnosis, using double-labelling flow cytometry with simultaneous determination of P-glycoprotein (PGP) expression and intracellular daunorubicin fluorescence (IDF). On the basis of pre-clinical results in multidrug-resistant K562 leukaemic cells, concentrations leading to iso-effective complete restoration of IDF were used: 5 and 10 micromol/l, respectively for PSC and CSA. In the clinical specimens, PGP expression was correlated with a significant decrease in IDE PSC was found to be significantly more potent than CSA since it was found to induce a significant increase in IDF in a higher number of cases and to a higher extent than CSA. PGP-unrelated activity of PSC was also observed in specimens expressing no PGP but exhibiting low IDF, thus probably expressing alternative resistance mechanisms. The results confirm the potency of PSC as MDR-modulating agent in clinical AML specimens whose resistance pattern differed from that of highly resistant cell models and suggest that the activity of PSC is not limited to P-glycoprotein inhibition.

Topics: Acute Disease; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Marrow; Cyclosporine; Cyclosporins; Daunorubicin; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Immunosuppressive Agents; Leukemia, Myeloid; Tumor Cells, Cultured

Multidrug resistance (MDR) mediated by the drug efflux pump P-glycoprotein (Pgp), may cause remission failure and relapse in patients with acute myeloid leukaemia (AML) by extruding cytotoxic agents such as anthracyclines from leukaemic cells thus allowing them to survive. Cell line data suggest that reversal of MDR is possible using modifying drugs such as cyclosporin A (CSA) and its analogue PSC 833. We have investigated the effects on cell kill of the addition of CSA and PSC 833 to daunorubicin, idarubicin, mitozantrone, etoposide and cytarabine in 52 fresh cell samples from AML patients using an MTT assay. Pgp status was determined by using monoclonal antibodies JSB-1 and MRK-16 and by assessment of rhodamine efflux. Although overall each cytotoxic-modifier combination produced significant improvements in cell kill compared to cytotoxic alone (P values ranged from P < 0.001 to P = 0.017), modifiers also produced significant cytotoxicity in their own right, and no consistent difference was seen between responses in Pgp-positive and negative groups. Up to one in three Pgp-positive samples failed to show any improvement in cell kill with the addition of CSA or PSC 833, possibly owing to co-expression of alternative resistance mechanisms not affected by the MDR modifiers. The best responses were seen when PSC 833 was added to idarubicin, with 7 out of 22 Pgp-positive cases (32%) showing five-fold improvements in cell kill or better compared to idarubicin alone. Comparison of equimolar concentrations of the two modifiers in the Pgp positive group failed to show a significant difference in cell kill, though PSC 833 was markedly superior to CSA in a minority of highly responsive samples which demonstrated clear evidence of MDR reversal. Our in vitro data suggest that MDR modifiers such as CSA and PSC 833 could play an important role in the therapy of AML and indicate the need for prospective randomised trials to assess their clinical efficacy.

Topics: Acute Disease; Adolescent; Adult; Aged; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Survival; Coloring Agents; Cyclosporine; Cyclosporins; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Drug Synergism; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Male; Middle Aged; Mitoxantrone; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured