pirarubicin and Leukemia

Topics: Aclarubicin; Anthraquinones; Antibiotics, Antineoplastic; Breast Neoplasms; Carubicin; Cell Survival; Daunorubicin; Doxorubicin; Drug Evaluation; Epirubicin; Heart; Humans; Idarubicin; Leukemia; Menogaril; Mitoxantrone; Naphthacenes; Nogalamycin; Sarcoma; Structure-Activity Relationship

Topics: Aclarubicin; Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Cytarabine; Doxorubicin; Humans; Interferon Type I; Leukemia; Middle Aged; Naphthacenes

(2'' R)-4'-O-Tetrahydropyranyl Adriamycin (THP) is a new antitumor agent discovered among series of similar anthracycline compound synthesized by Umezawa et al. Phase I study revealed dose limiting factor of leukopenia with upper GI toxicity. Alopecia, cardiac failure and transient hepatic failure were extremely mild. Definite responses were demonstrated in acute leukemia, lymphoma, ovarian carcinoma, head and neck carcinoma, breast carcinoma and GU carcinoma. Pharmacokinetic studies revealed rapid cell uptake and outputs in bile (20%) and urine (8%) in 24 hours. Transfer to third spaces were poor but definite. In vivo a part of THP was converted to ADM in the liver, but not in other tissues including tumors. THP would be an extremely interesting compound, because of comparable spectrum of responses to various tumors with extremely low toxicity compared with other anthracycline compounds.

Topics: Acute Disease; Clinical Trials as Topic; Doxorubicin; Gastrointestinal Diseases; Humans; Leukemia; Lymphoma; Neoplasms

Topics: Aclarubicin; Acute Disease; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Cytarabine; Doxorubicin; Humans; Interferon Type I; Leukemia; Middle Aged; Naphthacenes

Leukemia is a common malignancy affecting humans worldwide. Pirarubicin (Pira) is one of the anticancer agents used for the treatment of leukemia. Although Pira is effective, drug resistance may develop in cancer cells exposed to this drug, whereas the combination of natural products with Pira may help to overcome this problem. The aim of the present study was to focus on the effect of gallic acid (GA) on the anticancer activity of Pira in K562 leukemia cells and K562/doxorubicin (Dox)‑resistant leukemia cells in order to investigate the possible underlying mechanisms. The cell viability, mitochondrial activity, mitochondrial membrane potential (ΔΨm) and ATP levels were assessed in living K562 and K562/Dox cancer cells following treatment with GA/Pira combination, GA alone or Pira alone. P‑glycoprotein‑mediated efflux of Pira was determined in GA‑treated K562/Dox cancer cells. The results demonstrated that GA/Pira combination decreased cell viability, mitochondrial activity, ΔΨm and ATP levels in K562 and K562/Dox cancer cells in a GA concentration‑dependent manner compared with non‑treated or Pira‑treated cells. GA inhibited P‑glycoprotein‑mediated efflux of Pira in GA‑treated K562/Dox cancer cells. Therefore, GA enhanced the anticancer effect of Pira on K562 and K562/Dox cancer cells through cellular energy status impairment, and was able to reverse drug resistance in living K562/Dox cancer cells by inhibiting the function of P‑glycoprotein.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Survival; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Gallic Acid; Humans; K562 Cells; Leukemia

Clinical significance of antitumour drugs is limited by multidrug resistance (MDR). We examined the effect of bioreductive activation of the anthracyclines, doxorubicin (DOX) and pirarubicin (PIRA), by cytochrome P450 reductase (CPR) on triggering apoptosis of leukaemia HL60 cells and their MDR counterparts.. Cell cycle and FAS expression were investigated by flow cytometry. DNA fragmentation was examined by electrophoretic analysis and caspase-3/8 activities were determined colorimetrically.. Bioreductive activation of DOX and PIRA does not affect their ability to induce apoptosis of sensitive and resistant HL60 leukaemia cells.

Topics: Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 8; Cell Proliferation; Cell Survival; DNA Fragmentation; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; HL-60 Cells; Humans; Leukemia; NADPH-Ferrihemoprotein Reductase

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance is a decrease of steady state drug levels as compared to those in drug-sensitive controls. A variety of small molecules, such as verapamil and cyclosporin A, bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. The kinetics of P-glycoprotein-mediated efflux of various anthracycline derivatives was measured in multidrug-resistant (MDR) K562 cells in the presence of verapamil. Used for the purpose were daunorubicin, idarubicin and 8-S-fluoro-idarubicin which have the same pKa of deprotonation equal to 8.4, but different lipophilicity, 4'-epi-2'-bromo-daunorubicin which has a lipophilicity which is comparable to that of daunorubicin but a pKa equal to 6.3, pirarubicin with pKa equal to 7.7 and lipophilicity different from that of these derivatives were used. Our data show (1) that verapamil is unable to completely block the P-glycoprotein-mediated efflux of anthracyclines and that 10% of its functionality remains even with high verapamil concentrations, (2) that the ability of verapamil to restore intracellular accumulation of anthracyclines in MDR cells depends on the kinetics of their uptake. With fast kinetics uptake, as is the case for idarubicin, 8-S-fluoro-idarubicin, 4'-epi-2'-bromo-daunorubicin and pirarubicin (which have either a low pKa and/or high lipophilicity), verapamil can restore in multidrug resistant cells an intracellular drug level which is comparable to that observed in sensitive cells. This is not possible when the kinetics of uptake is low as is the case for daunorubicin. Cyclosporin A is a more potent modulator and is able to fully restore daunorubicin accumulation in multidrug resistant cells.

Topics: Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporine; Daunorubicin; Doxorubicin; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Idarubicin; Leukemia; Tumor Cells, Cultured; Verapamil

A number of small and lipophilic cations are able to reverse in vitro the resistance to anthracyclines and other natural products through their interaction with P-glycoprotein or P-gp. However, some modulators do not interact with P-gp. We have demonstrated in a previous a work, using confocal laser microspectrofluorometry, that quinine does not increase nuclear anthracycline uptake in multidrug-resistant Chinese hamster ovary LR73 cells. In this case the LR73 cells were transfected with the mdr1 gene. Moreover, quinine induced in these cells an increase of mdr1 gene expression. In the present study, we investigated verapamil and quinine for their ability to increase nuclear pirarubicin uptake in multidrug-resistant K562R and CEMR human leukemic cell lines. These two cell lines resist, respectively, to doxorubicin and vinblastine and both overexpress the P-gp. Verapamil was able to restore nuclear pirarubicin in both cell lines. On the other hand, quinine was unable to significantly increase nuclear pirarubicin uptake. Both modulators were able to restore pirarubicin sensitivity in both resistant cell lines. After treatment with quinine, mdr1 gene and P-gp expression was not significantly altered as observed previously in the LR73 cells. This suggest that the effect of quinine on mdr1 gene expression is dependent on the cell line studied. These data suggest that quinine could modify the molecular environment of anthracyclines and/or its binding to a possible cytoplasmic target, and that the mechanisms by which anthracyclines induce cell death, and ways by which chemotherapy fails in multidrug-resistant leukemic cells remain complex and are related to more than one target.

Topics: Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Death; Cell Nucleus; CHO Cells; Cricetinae; Doxorubicin; Drug Resistance, Multiple; Gene Transfer Techniques; Humans; K562 Cells; Leukemia

We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells.

Topics: Analysis of Variance; Antibiotics, Antineoplastic; Antineoplastic Agents; Biological Transport, Active; Blotting, Northern; Cyclosporine; Daunorubicin; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic; Genistein; HL-60 Cells; Humans; Isoflavones; Leukemia; RNA, Messenger; RNA, Neoplasm; Temperature; Time Factors; Tumor Cells, Cultured; Verapamil

The appearance of cellular resistance to antitumor drugs is a major problem in cancer chemotherapy. This results from the overexpression of the mdr 1 gene which encodes the 170 kDa P-glycoprotein or multidrug transporter. The uptake and release of 4'-O-tetrahydropyranyladriamycin by drug-sensitive and drug-resistant K562 cells in the different phase of the cycle have been determined. Synchronized cells were obtained by centrifugal elutriation. The kinetics, as well as the amount of drug intercalated inside the nucleus and free in the cytoplasm, have been determined using a spectrofluorometric method that we have developed and that does not compromise cell viability. The kinetics of active efflux of the drug under the effect of P-glycoprotein has been determined. We have calculated that the number of 4'-O-tetrahydropyranyladriamycin molecules, which are actively effluxed per cell and per second, is constant whatever the cell cycle phase.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Cycle; Cell Fractionation; Cytosol; Doxorubicin; Drug Resistance; G1 Phase; G2 Phase; Humans; Kinetics; Leukemia; Membrane Glycoproteins; Tumor Cells, Cultured

A phase II study of new anthracycline, THP, was conducted in 46 patients with hematological malignancies in a cooperative study. THP was given intravenously either at a dose of 13-34 mg/m2 for 3-5 consecutive days or 35-50 mg/m2 at 3-4 week intervals. Of 21 patients with acute leukemia, complete response (CR) was observed in 3 patients and partial response (PR) in 4. Of 22 patients with malignant lymphoma, CR was observed in 2 and PR in 6. The predominant toxicity was myelosuppression. Leukopenia was noted in 73% of patients and thrombocytopenia in 14%. Anorexia, nausea and vomiting were observed in 49%, 26% and 23%, respectively. Alopecia and acute cardiac toxicities were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for acute leukemia and malignant lymphoma.

Topics: Acute Disease; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Doxorubicin; Drug Evaluation; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged

THP-adriamycin (THP) is a new derivative of adriamycin (ADM) which is reported to have a lower cardiotoxicity than ADM. In this report, the effects of THP on cell growth, cell cycle traverse and colony-forming ability of RPMI-8402 cells were investigated in comparison with ADM. The growth-inhibitory effect of THP was equal or superior to that of ADM in this system. Analysis of the DNA histogram obtained by flow cytometry showed that THP exerted its growth-inhibitory effect by blocking cells at the G2 phase. At higher concentrations, THP inhibited the traverse of cells through the S phase and further through the whole cell cycle completely. These effects were quite similar to those of ADM, which suggested a similar mechanism of action for the two drugs from the aspect of the cell cycle. A follow-up study of cells accumulated at the G2 phase and a study on colony-forming ability revealed that the G2 phase accumulation was an irreversible and fatal effect of THP, so that G2-phase accumulation could be considered as a cytocidal effect of THP, indicating the clinical usefulness of this system for evaluation of the drug effect. From these results and the low cardiotoxicity, it was suggested that THP could be a good candidate for use as an antitumor agent in clinics.

Topics: Cell Cycle; Cell Division; Cell Line; Cells, Cultured; DNA, Neoplasm; Doxorubicin; Flow Cytometry; Humans; Interphase; Leukemia

A Phase II study of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was conducted in 162 patients with various hematological malignancies in a multi-institutional cooperative study. THP was given intravenously at a dose of either 10-30 mg/body for 3-5 consecutive days or 40-60 mg/body at 3-week intervals. Of 22 patients with AML, complete remission (CR) was observed in 2 patients and partial remission (PR) in 2. Of 18 patients with ALL, CR was observed in 5 and PR in 3. Of 68 patients with NHL, CR was observed in 11 and PR in 22. Of 8 patients with HD, CR was observed in 4 and PR in 2. One CML case showed CR and one ATL case showed PR. PR was noted in one of 2 patients with mycosis fungoides. Overall remission rate was 43.1% (CR 23 cases and PR 33 cases). The predominant toxicity was myelosuppression. Leukopenia (less than 4,000/mm3) was noted in 67 (77.6%) and thrombocytopenia (less than 10 X 10(4)/mm3) in 24 (27.0%). Nausea/vomiting and anorexia were common, and were observed in 61 (43.3%) and 65 (46.1%) cases, respectively. Hair loss and cardiotoxicity were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for various hematological malignancies including acute leukemia and malignant lymphoma.

Topics: Acute Disease; Adolescent; Adult; Aged; Anorexia; Antineoplastic Agents; Child; Doxorubicin; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia; Leukopenia; Lymphoma; Male; Middle Aged

Topics: Aclarubicin; Acute Disease; Adult; Antineoplastic Agents; Cytarabine; Doxorubicin; Drug Evaluation; Humans; Interferon Type I; Leukemia; Naphthacenes

Recently marked progress in many fields around the treatment of acute leukemia has resulted a marked improvement in the therapeutic results. Establishment of fundamental principles of therapy, i.e., understanding of remission induction, consolidation and maintenance has supported a systemic analysis of treatment. New antileukemia drugs such as Aclacinomycin, THP-adriamycin, Epirubicin, Mitoxantrone, Vindesine, Etoposide, PL-AC together with the immunotherapeutic agent i.e., Bestatin, kurestin and Nocardia-CWS were studied and found to show their merits in the treatment. Monitoring the patients by 5000 leukocyte differential or the development of new antibiotics or improvement of laminar air flow rooms etc, has supported the antileukemic therapy. Bone marrow transplantation, allogeneic, syngeneic or autologous, has shown a very rapid progress and is proved to be a reliable treatment with very high rate of complete cure.

Topics: Aclarubicin; Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Doxorubicin; Humans; Leukemia; Naphthacenes; Vincristine; Vindesine

The in vitro sensitivity of peripheral blood myeloblast clonogenic cells (CFU-MLs) to doxorubicin (DOX), aclacinomycin (ACL), and 4'-O-tetrapyranyl-doxorubicin (THP-DOX) was studied to evaluate the individual chemosensitivity of CFU-MLs. CFU-MLs from untreated patients were sensitive to the three tested anthracyclines (in 60% to 69% of the patients). Conversely, CFU-MLs from relapsed patients previously treated with DOX-containing regimens were sensitive to ACL and THP-DOX (in 71% and 75% of the patients, respectively) but resistant to DOX. Six of ten patients who entered complete remission with a combination of DOX, vincristine, and cytosine arabinoside had CFU-MLs in vitro which were sensitive to DOX. Conversely, none of the 13 patients resistant to this chemotherapy regimen displayed CFU-MLs which were sensitive in vitro to DOX. Nine of ten patients who responded to ACL as well as one of three resistant patients had CFU-MLs sensitive to ACL in vitro. No clinical responses were observed with THP-DOX in five of seven patients with CFU-MLs sensitive to this drug. The results indicate that myeloblast clonogenic assays can be used to predict the in vitro sensitivity of CFU-MLs to compounds with established antileukemic activity (ie, DOX, ACL). However, the discrepancy between in vitro and in vivo sensitivity to THP-DOX underlines the importance of knowledge of drug pharmacokinetics and the difficulty of using the CFU-ML test for screening new drugs.

Topics: Aclarubicin; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Doxorubicin; Humans; In Vitro Techniques; Leukemia; Naphthacenes; Neoplastic Stem Cells; Stem Cells; Tumor Stem Cell Assay