thioguanine-anhydrous and Breast-Neoplasms

Topics: Age Factors; Breast Neoplasms; Cell Movement; Clinical Enzyme Tests; Colonic Neoplasms; Cytarabine; Diagnosis, Differential; Doxorubicin; Drug Combinations; Drug Evaluation; Drug Evaluation, Preclinical; Fluorouracil; Humans; Kinetics; Leukemia; Mercaptopurine; Methods; Methotrexate; Models, Chemical; Neoplasms; Prognosis; Sarcoma; Testosterone; Thioguanine

6-Thioguanine (6-TG) is a purine analog that has marked variability in plasma concentration after oral administration. Following the development of a multiple-day i.v. regimen, we performed a phase II trial of this agent as first-line chemotherapy in women with metastatic breast cancer. Forty-one patients with measurable (31 patients) or evaluable (10 patients) disease were entered into this trial. 6-TG was administered i.v. over a 10 min period daily for 5 consecutive days, with a planned cycle length of 35 days. The daily dosage level was 55 mg/m2 in the first 15 patients, but this was increased to 65 mg/m2 in the remaining patients due to inadequate myelosuppression at the lower dose. Six patients, all with measurable disease, achieved a complete response (CR) (two patients) or a partial response (PR) (four patients). Three responses occurred at the 55 mg/m2 level and three at the 65 mg/m2 level. The 95% confidence interval (CI) for the true response rate among patients with measurable disease was 6-39%. The median time to progression was 140 days and median survival time was 460 days. The regimen was well tolerated. We conclude that 6-TG, as given in this study, has limited activity as first-line chemotherapy for women with metastatic breast cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Metastasis; Remission Induction; Survival Analysis; Thioguanine

To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors.. One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses.. Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients.. TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Female; Fluorouracil; Humans; Hydroxyurea; Lomustine; Lung Neoplasms; Male; Middle Aged; Mitolactol; Procarbazine; Prospective Studies; Thioguanine

The mutant frequencies (MF) at the HPRT locus of peripheral blood lymphocytes collected from breast cancer patients before and after treatment according to a defined protocol of the Institut Curie were compared to those from healthy donors. The treatment involved either a local radiotherapy (RT1) followed by a chemotherapy (CT2) or a chemotherapy (CT1) followed by a radiotherapy (RT2). In accord with others, we observed no significant difference in the MF to 6-thioguanine resistance (6TG) in T lymphocytes in the control and breast cancer groups before treatment. When the effect of CT or RT either alone or in combination was analysed, the increase observed in MF can be wholly accounted for by the effect of radiation. In this study, the effect of chemotherapy on mutation did not achieve significance. Circulating T lymphocytes are mainly in the G0 phase of the cell cycle and thus would not be mutated by drugs which preferentially affect dividing cells, whereas such cells could still mutate when submitted to ionizing radiation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cells, Cultured; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Resistance; Female; Fluorouracil; Humans; Hypoxanthine Phosphoribosyltransferase; Lymphocytes; Middle Aged; Mutagens; Mutation; Thioguanine

Thiopurines are in widespread clinical use for the treatment of immunological disorders and certain cancers. However, treatment failure due to resistance or adverse drug reactions are common, asking for new therapeutic strategies. We investigated the potential of 6-thioguanosine monophosphate (6sGMP) prodrugs to overcome resistance to 6-thioguanine. We successfully developed synthetic routes toward diverse 6sGMP prodrugs, tested their proliferation inhibitory potential in different cell lines, and examined their mode of action. Our results show that 4-acetyloxybenzyl- and

Topics: Breast Neoplasms; Female; Humans; Leukemia; Prodrugs; Purine Nucleosides; Thioguanine

Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.

Topics: Antimetabolites, Antineoplastic; Benzimidazoles; BRCA1 Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MCF-7 Cells; Niacinamide; Protein Kinase Inhibitors; Thioguanine

To detect the response of lymphocytes to radiation in untreated breast cancer patients with three different genetic assays.. Blood samples were collected from 25 untreated patients and 25 controls. Each blood sample was divided into two parts: one was irradiated by 3-Gy X-ray (irradiated sample), the other was not irradiated (non-irradiated sample). The radiosensitivity of lymphocytes was assessed by comet assay, cytokinesis-block micronucleus (CBMN) assay and 6-TG-resistant cells scored (TG) assay.. The baseline values of micronucleated cell frequency (MCF) and micronucleus frequency (MNF) in the patients were significantly higher than those in the controls (P < 0.01), and 3-Gy X-ray induced genetic damage to lymphocytes in the patients increased significantly as compared with that in the controls as detected with the three genetic assays (P < 0.01). The proportion of radiosensitive cases in the patient group was 48% for the mean tail length (MTL), 40% for the mean tail moment (MTM), 40% for MCF, 44% for MNF, and 48% for mutation frequencies of the hprt gene (Mfs-hprt), respectively, whereas the proportion of radiosensitive cases in the control group was only 8% for all the parameters.. The difference in the lymphocyte radiosensitivity between the breast cancer patients and the controls is significant. Moreover, there are wide individual variations in lymphocyte radiosensitivity of patients with breast cancer. In some cases, the radiosensitivity of the same patient may be different as detected with the different assays. It is suggested that multiple assays should be used to assess the radiosensitivity of patients with breast cancer before therapy.

Topics: Breast Neoplasms; Carcinogenicity Tests; Case-Control Studies; Comet Assay; Cytokinesis; Drug Resistance; Female; Humans; Lymphocytes; Micronucleus Tests; Middle Aged; Radiation Tolerance; Thioguanine; X-Rays

There are two well-described syndromes caused by tumor production of parathyroid hormone-related peptide (PTHrP), namely osteolytic bone disease associated with breast cancer and humoral hypercalcemia of malignancy (HHM) that occurs with or without bone metastasis. Both syndromes have been shown experimentally to be inhibited by neutralizing antibodies to PTHrP. In a search for small-molecule inhibitors of PTHrP production or effects, we have identified guanine-nucleotide analogs as compounds that inhibit PTHrP expression by human tumor cells associated with these syndromes. We show in nude athymic murine models that these compounds reduce PTHrP-mediated osteolytic lesions associated with metastatic human breast-cancer cells as well as the degree of hypercalcemia caused by excessive PTHrP production by a squamous-cell carcinoma of the lung. These results suggest that the PTHrP gene promoter may be a suitable target for treating the skeletal effects of malignancy.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cytokines; Female; Gene Expression; Guanine Nucleotides; Guanosine; Humans; Hypercalcemia; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Osteolysis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone-Related Protein; Peptide Hormones; Promoter Regions, Genetic; Thioguanine; Thionucleosides; Transplantation, Heterologous; Tumor Cells, Cultured

Induction of 6-thioguanine (TG) resistance by chemical mutagens was examined in a line of cells derived from a human epithelial teratocarcinoma cell clone. The cells, designated as P3 cells, have a stable diploid karyotype with 46(XX) chromosomes, including a translocation between chromosomes 15 and 20. Efficient recovery of TG-resistant mutants induced by the direct-acting mutagens: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG); 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10 -tetrahydrobenzo[a]pyrene (BPDE); and benzo[a]pyrene (B[a]P); activated in a cell-mediated assay, required an expression time of 7 days and a saturation density of 2 X 10(4) cells/60-mm petri dish. The TG-resistant mutant cells induced by MNNG and BPDE maintained their resistant phenotype 4-6 weeks after isolation. This mutant phenotype was associated with a more than 10-fold reduction in hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity relative to that of the parental P3 cell line, which was shown to catalyze the formation of 4.6 pmoles inosine-5'-monophosphate (IMP)/min/microgram protein. Induction of TG resistance was also observed in P3 cells cocultivated in a cell-mediated assay with human breast carcinoma cells, which are capable of polycyclic aromatic hydrocarbon (PAH) metabolism, after treatment with the carcinogenic PAHs: B[a]P, chrysene, 7,12-dimethylbenz[a]anthracene (DMBA), and 3-methylcholanthrene (MCA). The degree of mutant induction in this assay was related to the carcinogenic potency of these PAHs in experimental animals. The most potent mutagen was DMBA, followed in decreasing order by MCA, B[a]P, and chrysene. DMBA, at 0.4 microM, increased the frequency of mutants for TG resistance from 2 for the control to about 200 TG-resistant mutants/10(6) colony-forming cells (CFC). Benzo[e]pyrene (B[e]P) and pyrene, which are not carcinogenic, were not effective in the assay. None of the PAHs was mutagenic in the P3 cells cultivated in the absence of the PAH-metabolizing cells. These results indicate that the P3 cells can be useful for the study of mutagenesis at the HGPRT locus by direct-acting chemical mutagens, as well as by chemicals activated in a cell-mediated assay.

Topics: Biotransformation; Breast Neoplasms; Carcinogens; Cells, Cultured; Drug Resistance; Humans; Hypoxanthine Phosphoribosyltransferase; Mutagenicity Tests; Mutation; Teratoma; Thioguanine

Topics: Blood Cell Count; Breast Neoplasms; Drug Evaluation; Female; Humans; Middle Aged; Nausea; Neoplasm Metastasis; Neoplasm Recurrence, Local; Thioguanine; Time Factors

Topics: Breast Neoplasms; Drug Therapy, Combination; Humans; Middle Aged; Thioguanine; Vinblastine

Topics: Adult; Asparaginase; Breast Neoplasms; Cecal Diseases; Child; Cytarabine; Daunorubicin; Female; Fluorouracil; Humans; Intestinal Perforation; Leukemia; Male; Mercaptopurine; Methotrexate; Middle Aged; Necrosis; Prednisone; Thioguanine; Vincristine