sdz-psc-833 and dofequidar

New combination therapies against hematological malignancies have recently been reported. Anti-CD20 chimeric antibody adds a therapeutic benefit to standard-dose CHOP therapy without causing significant additional toxicity in the treatment of indolent B cell lymphoma. Multidrug resistant modifiers such as PSC833 and MS209 in combination with chemotherapy are useful for treating poor risk AML patients, whose leukemia/lymphoma cells express P-glycoprotein. Fludarabine containing FL and FLAG therapy were effective in patients with AML in relapse. The early addition of chemotherapy to ATRA, and maintenance therapy with chemotherapy and intermittent ATRA, can reduce the incidence of relapse in cases of acute promyelocytic leukemia.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cyclosporins; Cytarabine; Doxorubicin; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, B-Cell; Myelodysplastic Syndromes; Prednisone; Quinolines; Rituximab; Tretinoin; Vidarabine; Vincristine

Drug resistance is a major problem in cancer chemotherapy. P-glycoprotein plays a major role in multidrug resistance in cancer cells. P-glycoprotein is expressed in some normal tissues and has physiological functions. These include protecting the brain against toxic substances at the blood-brain barrier site, excreting toxic substances from the liver, kidney, and gastrointestinal tracts, and transporting steroidal hormones in the adrenal grand. Once expressed in cancer cells. P-glycoprotein effluxes a variety of anticancer drugs, such as doxorubicin, vinca alkaloids, etoposide and taxol, and thereby allows cancer cells to show resistance to these drugs.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Mitomycin; Quinolines

Since we discovered verapamil as an MDR-reversing agent in 1981, many MDR-reversing compounds have been reported. This type of drug must be very effective but minimal side effects. We recently found that MS-209 and PSC-833 to be reversing agents that interact directly with P-glycoprotein and show good MDR-reversing effect, both in vitro and in vivo. MS-209 and PSC-833 are thus interesting compounds for clinical use in future.

Topics: Animals; Antineoplastic Agents; Cyclosporins; Doxorubicin; Drug Resistance; Drug Synergism; Humans; Leukemia P388; Mice; Quinolines; Verapamil

The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Count; Cell Line, Transformed; Cell Line, Tumor; Cyclosporins; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Immunosuppressive Agents; Inotuzumab Ozogamicin; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Quinolines; Sialic Acid Binding Ig-like Lectin 2; Treatment Outcome; Tumor Cells, Cultured

The aim of this study was to explore whether (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is suitable to elucidate multidrug resistance and prediction of potentiation of antitumor agents by second-generation MDR1 inhibitors (PSC833, MS-209) in malignant brain tumors in rat. Malignant tumor cells (RG2 and C6 gliomas, Walker 256 carcinoma) were incubated with low dose vincristine (VCR) to induce multidrug resistance. MTT assay demonstrated a significant increase of surviving fractions in VCR-resistant sublines compared to those of drug-naive cells. Reverse transcriptase polymerase chain reaction revealed higher expression of MDR1 mRNA in VCR-resistant cells than drug-naive cells in each line. Volume distribution (V(d)) of (99m)Tc-MIBI was negatively correlated with MDR1 mRNA expression among drug-naive and VCR-resistant cells. MDR1 inhibitors decreased surviving fractions and increased V(d) of (99m)Tc-MIBI significantly in VCR-resistant sublines, whereas MDR1 mRNA expression was unchanged. These findings indicate that (99m)Tc-MIBI efflux was functionally suppressed by MDR1 inhibitors. Autoradiographic images of (99m)Tc-MIBI revealed higher uptake in drug-naive cells at basal ganglia compared with VCR-resistant cells at the opposite basal ganglia of rats. Oral administration of the second-generation MDR1 inhibitors significantly increased (99m)Tc-MIBI accumulation of both tumors. Therapeutic effects of VCR with or without the MDR1 inhibitors were also evaluated autoradiographically using (14)C-methyl-L-methionine ((14)C-Met) and MIB-5 index. (14)C-Met uptake and MIB-5 index of both tumors treated with VCR following the MDR1 inhibitor treatment significantly decreased compared with tumors treated with VCR alone. Analysis of (99m)Tc-MIBI accumulation is considered informative for detecting MDR1-mediated drug resistance and for monitoring the therapeutic effects of MDR1 inhibitors in malignant brain tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Autoradiography; Brain Neoplasms; Carcinoma 256, Walker; Cell Line, Tumor; Cell Proliferation; Cyclosporine; Cyclosporins; Cytotoxins; Drug Resistance, Neoplasm; Drug Synergism; Predictive Value of Tests; Quinolines; Radiopharmaceuticals; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Technetium Tc 99m Sestamibi; Tomography, Emission-Computed, Single-Photon; Vincristine

Recent studies in humans and mice have demonstrated that intestinal P-glycoprotein plays a causative role in the limited absorption of orally administered paclitaxel. Multidrug resistance (MDR)-reversing agents, such as cyclosporin A and PSC 833, are known to increase the systemic exposure to orally administered paclitaxel by enhancing absorption in the intestinal tract and decreasing elimination via the biliary tract. In this study, we demonstrated that coadministration of the MDR-reversing agent MS-209, which is known to inhibit P-glycoprotein function by direct interaction, improved the bioavailability of orally administered paclitaxel and consequently enhanced its antitumor activity.. The pharmacokinetics of paclitaxel were examined by measuring [(3)H]paclitaxel in plasma drawn from rats and mice given the drug with or without MS-209. The influence of MS-209 on the intestinal transport of [(3)H]paclitaxel was studied using a human colorectal cancer cell line, Caco-2. The in vivo efficacy of orally administered paclitaxel in combination with MS-209 was further evaluated in B16 melanoma-bearing mice.. The plasma concentration of [(3)H]paclitaxel following oral administration was significantly increased by coadministration of MS-209 at 100 mg/kg in both rats and mice. In rats, the AUC of [(3)H]paclitaxel following oral administration was strikingly increased (1.9-fold) by coadministration of MS-209, whereas the AUC of [(3)H]paclitaxel following i.v. injection was slightly increased (1.3-fold) by MS-209. The increase in apparent bioavailability of oral paclitaxel due to MS-209 was 1.4-fold. To demonstrate this enhancing action in vitro, we studied the influence of MS-209 on the transport of [(3)H]paclitaxel using Caco-2 cells, which is a well-known model of intestinal efflux. The transport of [(3)H]paclitaxel across the Caco-2 monolayer was markedly inhibited in the presence of MS-209, and the apparent K(i)of MS-209 for the active transport of [(3)H]paclitaxel was 0.4 microM. Moreover, paclitaxel administered orally at 100 mg/kg per day with MS-209 at 100 mg/kg per day showed significant antitumor activity in B16 melanoma-bearing mice, whereas paclitaxel administered orally alone at the same dose showed no antitumor activity. These results suggest that the coadministration of MS-209 improved low systemic exposure to paclitaxel through inhibition of P-glycoprotein, which is involved in drug excretion via the intestinal tract, resulting in a clear antitumor activity of paclitaxel administered orally.. The present study suggests that coadministration of MS-209 may be a useful way to improve the bioavailability of drugs not suitable for oral administration due to elimination via the intestinal tract.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Caco-2 Cells; Cyclosporine; Cyclosporins; Humans; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Paclitaxel; Quinolines; Rats; Rats, Sprague-Dawley

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 emergence of multidrug resistance (MDR) is a major problem in cancer chemotherapy. Many compounds have been developed to reverse MDR, and some of them are undergoing clinical trials. Among them, MS-209, a novel quinoline derivative, is one of the most potent MDR-reversing agents: MS-209 at 3 microM effectively reverses MDR in various cell lines in vitro. MS-209 directly interacts with P-glycoprotein (Pgp) and inhibits Pgp-mediated drug transport. Oral administration of MS-209 combined with anticancer drugs significantly increases the life span of mice bearing MDR tumor cells without causing serious side effects. SDZ PSC 833, a non-immunosuppressive analogue of cyclosporin A (CsA), is another potent MDR-reversing drug. Interestingly, the MDR-reversing activity of SDZ PSC 833 is enhanced in vitro and in vivo by MRK-16, a monoclonal antibody that recognizes an extracellular epitope of Pgp. Since MRK-16 promotes immune responses to MDR tumor cells expressing Pgp, the combined use of MRK-16, SDZ PSC 833, and antitumor drugs could be an effective therapeutic modality to reverse MDR.

Topics: Animals; Antineoplastic Agents; Cell Division; Cyclosporins; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Quinolines; Tumor Cells, Cultured