pirarubicin and Leukemia--Myeloid

A 40-year-old woman, who had suffered from AML (M1) in 1983, developed ovarian cancer (stage IIIc) in December 1996 after long-term remission. She underwent surgical resection of the cancer, 10 courses of standard chemotherapy and tandem PBSCT (total dose: CBDCA 6,750 mg, CDDP 200 mg, CPA 16,000 mg, THP-ADR 450 mg). After receiving the last course of chemotherapy in June 1998, she was referred to our hospital in September 1998 because of pancytopenia. Laboratory findings showed pancytopenia with 34% leukemic cells, which were positive for alpha NBE and negative for POX and CAE. Surface-marker analysis of the leukemic cells showed positivity for CD11c, CD33, CD56, and DR, and chromosome analysis revealed 47, XX, +8. The patient was diagnosed as having AML (M5a), and received induction therapy consisting of IDR and Ara-C, which led to complete remission. As she had not received etoposide, this case was thought to have been therapy-related leukemia due to the platinum agents used for treating the ovarian cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Leukemia, Myeloid; Neoplasms, Second Primary; Ovarian Neoplasms

On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study.. All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine.. A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9%, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009).. The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Disease-Free Survival; Down Syndrome; Doxorubicin; Etoposide; Female; Humans; Induction Chemotherapy; Infant; Japan; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Prospective Studies

Various methods of intensive chemotherapy have contributed to an improved survival in pediatric acute myeloid leukemia (AML). We here report the long-term results of the two consecutive trials of Tokyo Children's Cancer Study Group (TCCSG), incorporating repetitive use of high-dose cytarabine (HD-Ara-C) based combination chemotherapy in post-remission phase.. A total of 216 eligible children with newly diagnosed AML were treated in the two consecutive multi-center trials of TCCSG, M91-13 and M96-14, from August 1991 to September 1998. In M91-13 trial, patients received eight courses of intensive post-remission chemotherapy, including six HD-Ara-C containing courses, after remission-induction therapy. Autologous hematopoietic stem cell transplantation (HSCT) could be selected by physician's choice, and allogeneic HSCT was allocated if donor was available. In M96-14 trial, the last two HD-Ara-C courses were omitted from the chemotherapy arm.. The remission-induction rate was 88.8% and probability of 5-year Overall survival (OS) and event-free survival (EFS) were 62% (56-69% with 95% Confidence intervals (CIs)) and 56% (49-62%), respectively. Treatment-related mortality (TRM) was 7.8%. Among patients without Down syndrome (DS) or acute promyelocytic leukemia (APL), the presence of t(8;21) or inv(16) was a significant good prognostic factor both in the univariate and multivariate analyses. Children with DS (N = 10) and APL (N = 14) also showed a good survival exceeding 70% in 5 years.. These results suggest that repetitive use of HD-Ara-C was effective and safe for childhood AML. However, further optimization of AML therapy is required.

Topics: Acute Disease; Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Disease-Free Survival; Down Syndrome; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Hydrocortisone; Infant; Infections; Japan; Kaplan-Meier Estimate; Leukemia, Myeloid; Male; Methotrexate; Mitoxantrone; Remission Induction; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Tretinoin; Vincristine

We examined the effect of selected anthraquinone antitumour agents - doxorubicin (DOX), pirarubicin (PIRA) and benzoperimidine BP1 - on inducing apoptosis of the sensitive leukaemia HL60 cell line and its multidrug resistance sublines overexpressing P-glycoprotein (HL60/VINC) and multidrug resistance-associated protein 1 (HL60/DOX). All agents used at IC50 and IC90 were able to influence the cell cycle of sensitive HL60 and resistant cells and induce apoptosis. Interestingly, it was seen that HL60/VINC cells were more susceptible to undergo caspase-3/caspase-8-dependent apoptosis induced by the studied anthraquinone compounds compared with HL60 and HL60/DOX cells. However, the examined agents did not change the expression of Fas receptors on the surface of HL60-sensitive and-resistant cells.

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Caspase 8; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; fas Receptor; Gene Expression; Heterocyclic Compounds, 4 or More Rings; HL-60 Cells; Humans; Leukemia, Myeloid

Confocal microspectrofluorometry allows the analysis of fluorescent molecules such as anthracylines in isolated living cells. An optical microscope fitted with a phase-contrast 100 X water-immersion objective enables simultaneous observation of the sample, focusing of the laser beam on the selected cell fraction (nucleus) and collection of the fluorescence emitted from the sample. The resulting intranuclear spectra are interpreted according to a quantitative model of the fluorescence spectra of both free and DNA-bound anthracycline. The intranuclear drug concentration can thus be determined. This technique has been applied to blast cells collected in patients with acute leukemia. Leukemic cells are aspirated from bone marrow, separated by Ficoll sedimentation and resuspended in RPMI-1640 containing 10% fetal calf serum and 200 nM tetrahydropyranyl-doxorubicin (THP-DOX). After one hour, 20 cells are analyzed and the mean nuclear drug content is determined (C1). Cells are then resuspended in the same medium but without anthracycline for 3 hours and the mean intranuclear drug concentration is then also determined (C3). From C1 and C3 the retention rate (RR) is calculated. Firstly, the accuracy of the method was checked. In 4 AML patients, two different samples aspirated on the same day were divided into two portions. Thus, two measurements were made on each one (4 values per patient). Coefficients of variation were satisfactory (4, 6, 12, and 12%). Secondly, blast cells collected in patients with AML and ALL at diagnosis or in relapse were studied. P-glycoprotein (P-gp) and CD34 expression was also studied using respectively immunohistochemistry land flow cytometry. Results obtained from the first 21 patients showed that there was no correlation between RR and either P-gp or CD34 expression. This could result from the efflux of THP-DOX by other mechanisms and/or low sensitivity of the staining technique.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antigens, CD34; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Bone Marrow; Cell Nucleus; Child; Doxorubicin; Drug Resistance, Multiple; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid; Microscopy, Confocal; Microspectrophotometry; Middle Aged; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma

For the purpose of establishing a method for reasonable clinical use of anthracyclines in leukemia chemotherapy, we examined the pharmacokinetics and the mode of action with five anthracyclines such as daunorubicin (DNR), doxorubicin (DOX), aclarubicin (ACR), THP adriamycin (THP), idarubicin (IDA). In the patients with AML, blood ACR or IDA level increased and then disappeared very rapidly after iv bolus injection. In contrast, their metabolites (M1 or IDAol) increased for up to 2 or 4 hrs and remained much longer than ACR or IDA. The concentration of ACR, IDA or their metabolites were found to be much higher in the leukocyte fraction than in erythrocyte fraction or plasma. In HL60 cell suspension, anthracyclines were rapidly accumulated into the cells, and the uptake of IDA or THP were higher than the other agents. In HL60 cells, anthracyclines accumulated in the nuclear fraction but ACR was accumulated markedly in the cytosol fraction. From the result of DNA binding assay, binding at excess to calf thymus DNA of ACR was suggested to be approximately 2 times higher than that of other agents. DNA strand brakes in HL60 cells treated with anthracyclines were shown by pulse field gel electrophoresis, and IDA was found to have stronger activity to cause the DNA strand breaks. In conclusion, it seemed that anthracyclines showed similar action mechanisms, but in some respects quantitative differences were existed among them. Anthracyclines should be given to patients based on their pharmacological characteristics to obtain higher remission rate and suppress resistant cells.

Topics: Aclarubicin; Acute Disease; Antibiotics, Antineoplastic; Daunorubicin; DNA; DNA Damage; DNA Replication; Doxorubicin; Humans; Leukemia, Myeloid

The combined effects of pirarubicin (THP) and various antitumor drugs on HeLa S3 human uterine cervix carcinoma and K562 human myelocytic leukemia cells were determined by enhancement of their cytotoxic activities. The combination of 0.15 microgram/ml THP with cisplatin (CDDP), mitomycin C (MMC), peplomycin (PEP), 5-fluorouracil (5-FU), methotrexate (MTX), enocitabine (BH-AC) or etoposide showed synergistic effects on HeLa S3 cells. Also, the combination of 0.01 microgram/ml THP with CDDP, BH-AC or etoposide showed synergistic effects on K562 cells. Especially, the combined effects of THP with MMC or MTX were remarkable, and the combination under almost all concentrations of MMC or MTX showed synergistic effects on HeLa S3 cells. On the other hand, the combination of adriamycin (ADM) with MMC or MTX did not show such a remarkable effects on HeLa S3 cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Etoposide; Female; Humans; Leukemia, Myeloid; Methotrexate; Mitomycin; Mitomycins; Tumor Cells, Cultured; Uterine Cervical Neoplasms

Accumulation, cytotoxicity, and DNA damages produced by doxorubicin (DOX), pirarubicin (THP-DOX), fluoro-doxorubicin (ME2303) or its isolated metabolite M1 have been investigated in human myelogenous leukemia cells, sensitive (K562) and resistant to DOX (K562/DOX). These compounds differed by lipophilicity and/or sugar moiety either with (DOX, THP-DOX) or without (ME2303, M1) amino group. In K562 cells, the cytotoxicity was correlated to DNA single-stranded breaks and the intracellular drug amount of DOX or M1. This was not true when the cells were treated with THP-DOX or ME2303. In addition, THP-DOX produced total DNA protein cross-linking. In K562 cells DNA damage was not repaired, while in K562/DOX repair of DNA damage produced by all drugs could be observed. Although in K562/DOX cells drug accumulation was much reduced, higher intracellular drug concentration was required to induce similar level of cytotoxicity and DNA damage. Thus, cytotoxicity produced by anthracycline is not always associated with DNA damage. Different level of resistance to DOX, THP-DOX, ME2303 or M1 is associated with reduced drug accumulation which varies with the structure.

Topics: Antibiotics, Antineoplastic; Cell Line; Cell Survival; DNA Damage; DNA, Neoplasm; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia, Myeloid; Structure-Activity Relationship; Tumor Cells, Cultured