thioguanine-anhydrous and Neoplasm-Metastasis

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

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Thioguanine

In a randomized multi-institutional trial of the Eastern Cooperative Oncology Group, 316 patients with advanced measurable colorectal adenocarcinoma were treated with a weekly schedule of 5-fluorouracil given orally and intravenously with oral-5-fluorouracil in combination with cyclophosphamide or 6-thioguanine, or with oral Methyl CCNU administered once every eight weeks. On failure or progression, 133 protocol patients crossed-over to a secondary therapy, while 116 other patients previously treated with 5-fluorouracil off protocol were randomized to treatment with Methyl CCNU or B-2'-deoxythioguanosine. Response rates among patients who had received no prior chemotherapy were 18% to oral 5-FU, 15% to intravenous 5-FU and to MeCCNU, 12% to 5-FU and 6-thioguanine and 5% to cyclophosphamide and 5-FU, with little activity (3% response rate) in crossover or previously treated patients. Treatment with 5-FU, particularly oral 5-FU was associated with the least drug-related toxicity. Hematologic toxicity was greatest with Methyl CCNU, but was no more frequent in previously treated than in untreated patients. A tendency toward cumulative bone marrow depression was noted. 5-FU was effective only in ambulatory patients, whereas responses among non-ambulatory patients were seen only in the group treated with Methyl-CCNU.

Topics: Adenocarcinoma; Antineoplastic Agents; Bone Marrow; Clinical Trials as Topic; Colonic Neoplasms; Cyclophosphamide; Deoxyguanosine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Neoplasm Metastasis; Rectal Neoplasms; Semustine; Thioguanine; Thionucleosides

To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-based medicine.. By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0 software was used to conduct meta-analysis of the outcome indicators of the included literature.. This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical direction for clinical treatment.. The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals.. PROSPERO (registration number is CRD42020150466).

Topics: Adolescent; Antimetabolites, Antineoplastic; Child; Child, Preschool; Drug Substitution; Humans; Infant; Mercaptopurine; Meta-Analysis as Topic; Neoplasm Metastasis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Randomized Controlled Trials as Topic; Recurrence; Research Design; Systematic Review as Topic; Thioguanine

The various members of the Trk tyrosine kinase family and p75 neurotrophin receptor (p75(NTR)) have been identified as signaling receptors for the structurally related members of the neurotrophins (NT) family. We have previously reported that NT treatment of murine and human brain-metastatic melanoma cells affects their invasive capacities and increases the production of extracellular-matrix degradative enzymes. These cells express aberrant levels of functional p75(NTR) and TrkC, the putative high-affinity receptor for the neurotrophin NT-3. Here we demonstrate that, by using sensitive immune-complex kinase assays in human brain-metastatic (70W) melanoma cells, TrkC receptors associate with a kinase activity exhibiting a dose-dependent susceptibility to inhibition by the purine-analogs 6-thioguanine and 2-aminopurine. The activity of this purine-analog-sensitive kinase (PASK) was induced by NT-3 in a time-dependent fashion, phosphorylating exogenous myelin basic protein (MBP) but not denatured enolase. It is similar to the one reported to relate with p75(NTR) and TrkA receptors and stimulated by the prototypic NT, nerve growth factor. Thus, PASKs may represent unique signaling components common to NT receptors that could engage joint downstream signaling effectors in brain-metastatic melanoma.

Topics: 2-Aminopurine; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Melanoma; Neoplasm Metastasis; Neurotrophin 3; Protein Kinases; Protein Serine-Threonine Kinases; Receptor, Nerve Growth Factor; Receptor, trkC; Receptors, Nerve Growth Factor; Signal Transduction; Thioguanine; Time Factors

For many cancer patients, removal of primary tumor is curative; however, if metastatic lesions exist and are not responsive to treatment, survival is limited. Although immunotherapy is actively being tested in animal models against primary tumors and experimental metastases (i.v. induced), very few studies have examined immunotherapy of spontaneous, established metastatic disease. The shortage of such studies can be attributed to the paucity of adequate animal models and to the concern that multiple metastatic lesions may be more resistant to immunotherapy than a localized primary tumor. Here, we use the BALB/c-derived mouse mammary carcinoma, 4T1, and show that this tumor very closely models human breast cancer in its immunogenicity, metastatic properties, and growth characteristics. Therapy studies demonstrate that treatment of mice with established primary and metastatic disease with MHC class II and B7.1-transfected tumor cells reduces or eliminates established spontaneous metastases but has no impact on primary tumor growth. These studies indicate that cell-based vaccines targeting the activation of CD4+ and CD8+ T cells may be effective agents for the treatment of malignancies, such as breast cancer, where the primary tumor is curable by conventional methods, but metastatic lesions remain refractile to current treatment modalities.

Topics: Animals; Antimetabolites, Antineoplastic; B7-1 Antigen; Cancer Vaccines; Cell Division; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens Class II; Immunotherapy, Active; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; T-Lymphocytes; Thioguanine; Transfection

We have measured the forward mutation rate at the hypoxanthine phosphoribosyltransferase (HPRT) gene of the human promyelocytic leukemia cell line HL-60 and have determined the molecular spectrum of spontaneous HPRT mutations in 45 independent 6-thioguanine-resistant HL-60 sublines. Four fluctuation tests using a total of 132 replicate HL-60 cultures revealed a mean forward mutation rate of HL-60 cells to thioguanine resistance of 1.7-6 x 10(-7)/cell/generation. Blot hybridization analysis of the X-linked HPRT gene using a human HPRT complementary DNA probe revealed abnormalities in HPRT gene structure and/or HPRT mRNA expression in 24 of 45 (53%) independent thioguanine-resistant HL-60 sublines. Six different classes of mutation were identified. The most prevalent (47%; 21 of 45 mutations) consists of mutations that are not detected by blot hybridization analyses and that do not disrupt HPRT mRNA production. These results suggest that a comparatively low forward mutation rate may be found in malignant human cells that exhibit both karyotypic and molecular evidence of genomic instability and that several different molecular classes of mutation may contribute to thioguanine resistance in HL-60, and perhaps in other, malignant human cells. The forward mutation assay system we have developed using the X-linked HPRT gene of HL-60 cells may be useful for analyses of the mutagenic potential and molecular spectrum of mutations produced by chemotherapeutic agents, suspected human mutagens and carcinogens, and phagocyte respiratory burst oxidants in human cells.

Topics: Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Promyelocytic, Acute; Mutation; Neoplasm Metastasis; Oxygen Consumption; Phagocytes; RNA, Messenger; Thioguanine; Tumor Cells, Cultured; X Chromosome

Topics: Animals; Macrophage Activation; Mammary Neoplasms, Experimental; Methotrexate; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Thioguanine

Spontaneous mutation rates were determined in mouse mammary tumor subpopulation lines that differ in metastatic phenotype. Although there was almost a 9-fold difference in spontaneous rates to ouabain resistance among the three lines tested, the difference did not correlate with ability to metastasize. Similarly a 10-fold difference in spontaneous rates to 6-thioguanine resistance did not correlate with metastatic ability. In contrast, the frequency of ethyl methanesulfonate-induced mutations was associated with metastatic potential. Thus, ethyl methanesulfonate only induced significant numbers of 6-thioguanine resistant colonies in 66 and 410.4 cells, the only 2 of 5 lines tested that spontaneously metastasize at high frequency, and of ouabain resistant colonies in 66, 410.4, and 168 cells, the only lines tested that produce experimental lung metastases after i.v. injection. Differential sensitivity to induced mutation was not correlated with differences in plating efficiency, wild type sensitivity to ethyl methanesulfonate, 6-thioguanine, or ouabain toxicity, ploidy, cell shape, cell size, or ability to engage in metabolic cooperation.

Topics: Animals; Cell Count; Cell Line; Drug Resistance; Ethyl Methanesulfonate; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mutation; Neoplasm Metastasis; Ouabain; Thioguanine

Topics: Animals; Cell Line; Clone Cells; Drug Resistance; Mice; Mutation; Neoplasm Metastasis; Neoplasms, Experimental; Ouabain; Thioguanine

The relationship between immune complex (IC) formation and tumor cell metastatic potential was investigated in rats inoculated in the footpad with parental 13762 mammary adenocarcinoma cells or 6-thioguanine-resistant (TGR) variant cells. These cell lines are either highly metastatic (13762), nonmetastatic (TGR), or occasionally metastatic ( TGRrev , TGRrevM ). The 13762 TGR rat tumor model thus provides the opportunity to examine host immune responses to tumor cells of different phenotypes, but derived from the same parent tumor line. IC levels were low in 13762 tumor-bearing rats. In contrast, animals with TGR tumors had high levels of ICs in their sera, while animals bearing TGRrev and TGRrevM tumors had intermediate levels of ICs. In this rat tumor model system, IC formation is inversely related to the metastatic potential of the tumor lines.

Topics: Adenocarcinoma; Animals; Antigen-Antibody Complex; Cell Line; Drug Resistance; Female; Mammary Neoplasms, Experimental; Neoplasm Metastasis; Rats; Rats, Inbred F344; Thioguanine

A 6-thioguanine resistant (TGR) variant of the highly tumorigenic and metastatic mammary adenocarcinoma cell line 13762 was obtained. This variant was no longer tumorigenic or metastatic in normal syngeneic rats but did grow as a primary tumor in irradiated animals. Our results suggest that the TGR cell line was rejected by an irradiation-sensitive immunological mechanism. Although the TGR cells produced primary tumors in irradiated animals, there was no evidence of the extensive metastasis seen with the 13762 cells. This apparent inability to metastasize was confirmed by injecting the TGR cells intravenously. Whereas the 13762 cells produced large numbers of metastatic lung foci, there was no evidence of lung metastasis with the TGR cells, even in irradiated animals. Revertant cells for the 6-thioguanine-resistant phenotype were still non-tumorigenic and non-metastatic in normal rats, suggesting that 6-thioguanine resistance is not associated with the altered tumorigenic phenotype. From the TGR variant, cell lines were selected with an increased ability to produce tumors in normal rats. Although some of these revertants were capable of producing limited lung metastases in normal animals, extensive metastases were always seen when the cells were injected into irradiated animals. Differences between the 13762 and the TGR variants were also found in their ability to produce plasminogen activator. The TGR cells released far less plasminogen activator in culture than the 13762 cells. This could be a contributing factor in their different metastatic potentials.

Topics: Adenocarcinoma; Animals; Cell Line; Dose-Response Relationship, Drug; Drug Resistance; Female; Immunosuppression Therapy; Mammary Neoplasms, Experimental; Neoplasm Metastasis; Plasminogen Activators; Rats; Rats, Inbred F344; Thioguanine

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

Beta-thioguanine deoxyriboside (betaTGdR) is a purine nucleoside derivative which was studied alone or in combination with arabinosyl cytosine (Ara-C) in patients with solid tumors and acute leukemia. No significant responses were observed in 22 patients with solid tumors. The response rate with betaTGdR alone in acute leukemia was 26% and in combination with Ara-C was 24%. Responses were generally of short duration. Toxicity included myelosuppression, nausea, stomatitis, hyperpigmentation, photosensitivity, and liver function abnormalities.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Cytarabine; Deoxyguanosine; Deoxyribonucleosides; Drug Therapy, Combination; Female; Guanosine; Humans; Leukemia; Leukopenia; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Remission, Spontaneous; Thioguanine; Thionucleosides; Thrombocytopenia; Time Factors

Eighty-six children with non-Hodgkin's lymphoma were studied from 1964 to January 31, 1975. Seventy-six percent of the 43 patients in the nonprotocol group had far advanced disease, and 76% had Rappaport's diffuse histology. Only 11% of these patients survived free of disease. The second group of 43 patients received the LSA2L2 protocol. Seventy-six percent had advanced disease and 86% diffuse histology. Of these patients 76% are surviving free of disease with a median observation time of 25+ months. Fifty-one percent of the survivors are off therapy and without evidence of disease. Prognostic factors such as primary sites, stages, histology, and others are discussed. The most important prognostic factor is early and aggressive therapy, and the achievement of a complete response status within 1-2 months from onset of therapy.

Topics: Adolescent; Antineoplastic Agents; Asparaginase; Carmustine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Dactinomycin; Daunorubicin; Drug Therapy, Combination; Female; Humans; Hydroxyurea; Lymphoma; Male; Mercaptopurine; Methotrexate; Neoplasm Metastasis; Prednisone; Thioguanine; Vinblastine; Vincristine

In a study of non-Hodgkin's lymphoma in children, 104 children were treated and followed at Memorial Sloan-Kettering Cancer Center from 1964 throughout June 1974. Forty-three patients, previously treated and untreated, received a nonspecific group of various chemotherapeutic agents and attained an 11% disease-free survival rate. A second group of 18 previously untreated patients, who received a chemotherapeutic regimen consisting of cyclophosphamide alone, achieved a 33% disease-free survival rate. The last group, 43 previously untreated patients (77% of whom had far advanced disease and 86% of whom had diffuse histological types) who received a new and intensive multiple-drug regimen (the LSA2-L2 protocol) consisting of induction, consolidation, and maintenance phases, has maintained an 81% disease-free survival rate after a median observation time of 21+ months. Although nervous system involvement and recurrence or metastases at any time are poor prognostic factors, initial marrow involvement and the amount of bulky disease are no longer considered negative prognosticators when intensive treatment is initiated immediately after diagnosis, is continued for 2--3 years, and includes radiation therapy to sites of bulky disease and CNS prophylaxis. The LS2-L2 treatment is effective in accomplishing the dual aims of not only increasing the numbers of disease-free patients but also prolonging their survival.

Topics: Adolescent; Asparaginase; Bone Marrow; Brain Neoplasms; Carmustine; Child; Child, Preschool; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Humans; Hydroxyurea; Lymphoma; Male; Methotrexate; Neoplasm Metastasis; Nitrogen Mustard Compounds; Peripheral Nervous System Neoplasms; Prednisone; Prognosis; Thioguanine; Vincristine

Topics: Animals; Antineoplastic Agents; Child; Cyclohexanes; Cyclophosphamide; Cytarabine; Dactinomycin; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Humans; Imidazoles; Leukemia L1210; Lung Neoplasms; Melanoma; Mice; Neoplasm Metastasis; Neoplasms; Neoplasms, Experimental; Nitrogen Mustard Compounds; Nitrosourea Compounds; Thioguanine; Triazenes; Wilms Tumor

Topics: Aged; Antineoplastic Agents; Blood Coagulation; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cyclophosphamide; Drug Therapy, Combination; Fibrinogen; Fluorouracil; Heparin; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Radiography; Skin Neoplasms; Thioguanine; Vincristine

Topics: Aged; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cyclophosphamide; Fibrinogen; Fluorouracil; Heparin; Humans; Lung Neoplasms; Methotrexate; Middle Aged; Neoplasm Metastasis; Thioguanine; Vincristine