thioguanine-anhydrous and Sarcoma-180

The expression of alkaline phosphatase (AP) was analyzed in multidrug-resistant (MDR) tumor cells (sarcoma 180, lung carcinoma, and renal cell carcinoma cell lines) by means of immunocytochemistry. MDR cell cultures showed an overexpression of AP and a cross-resistance to 6-thioguanine (6-TG, CAS 154-42-7). Significant correlations between AP expression and doxorubicin or vincristine resistance and P-glycoprotein (P-170) expression were found in these cell cultures. A specific AP inhibitor, levamisole, reversed resistance to 6-TG, but not to doxorubicin. This indicates that 6-TG resistance is certainly associated to P-170 but a causal function of AP for the development of MDR does not exist.

Topics: Alkaline Phosphatase; Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Division; Doxorubicin; Drug Resistance; Humans; Immunohistochemistry; Levamisole; Mice; Radioimmunoassay; Sarcoma 180; Thioguanine; Tumor Cells, Cultured; Vincristine

6-Methylmercaptopurine ribonucleoside (6-MMPR), an inhibitor of purine nucleotide biosynthesis de novo, was used as a model compound to evaluate the relationship between the levels of intracellular guanosine triphosphate (GTP) and the formation of cellular glycoproteins and their dolichol-oligosaccharide precursors in Sarcoma 180 cells. Previous studies using the purine antimetabolite, 6-thioguanine (6-TG), demonstrated a relationship between the drug-induced decrease in GTP levels and the incorporation of radiolabelled mannose and fucose into cellular glycoproteins; estimation of the importance of these cell-surface alterations to the cytotoxicity produced by this agent was complicated by the incorporation of 6-TG nucleotides into cellular DNA and RNA. In this report, evidence is presented to show that the toxicity of 6-MMPR to Sarcoma 180 cells is associated with the effects of this agent on the intracellular pools of purine nucleotides. GTP functions in part in the activation of the sugar mannose, a step necessary for the biosynthesis of glycoproteins from nucleotide sugar precursors. Thus, 6-MMPR, which blocks the de novo pathway of purine nucleotide biosynthesis, caused a pronounced decrease in the intracellular pools of GTP in Sarcoma 180 cells; this phenomenon was accompanied by a marked reduction in the incorporation of radiolabelled mannose into cellular glycoproteins and their dolichol-linked oligosaccharide precursors. In contrast, the incorporation of glucosamine, a sugar not metabolically activated by GTP, into glycoproteins, and of leucine into protein, were depressed only after prolonged incubation with either 6-MMPR or 6-TG. Adenine restored purine nucleotide pools depleted by 6-MMPR and partially prevented both the reduction in mannose incorporation into glycoprotein and the cytotoxic effects of this antimetabolite. Guanosine partially reversed the effects of 6-MMPR on intracellular GTP pools and mannose incorporation but not the depression of ATP pools produced by this anti-metabolite. However, guanosine did not reverse the cytotoxicity of 6-MMPR but instead enhanced its toxicity. The findings are consistent with the possibility of membrane changes being involved in the cytotoxicity of 6-MMPR, but clearly other factors are involved as well.

Topics: Adenosine Triphosphate; Animals; Cells, Cultured; Diterpenes; Dolichols; Glycoproteins; Guanosine; Guanosine Triphosphate; Inosine; Mannose; Methylthioinosine; Oligosaccharides; Sarcoma 180; Thioguanine

Topics: Alkaline Phosphatase; Animals; Cells, Cultured; Drug Resistance; Female; Hypoxanthine Phosphoribosyltransferase; Mice; Mice, Inbred Strains; Phosphoribosyl Pyrophosphate; Sarcoma 180; Thioguanine

Antitumor activity and toxicity to host of newly synthesized disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in murine ascites sarcoma-180 system (total packed cell volume method) by parenteral administration. The compounds tested were 6-alkyl disulfides (carbon number of alkyl group: 2, 3, 4, 5, 6, 7, 8, 10, and 14), 6-branched-alkyl disulfides (iso-propyl, sec-butyl, and tert-butyl), and 6-aralkyl disulfide (naphthyryl). Most disulfide derivatives of 6-MP and 6-TG showed higher antitumor activity (lower ED50) and higher toxicity to host (lower LD50) than parent compounds, but ratios of increase in activity and toxicity were different with each other. The compounds with higher chemotherapeutic index (LD50/ED50) than parent compounds were alpha-naphthyryl (8.7) disulfide in a series of 6-MP (7.5) derivatives; and sec-butyl (27), tert-butyl (24), octyl (23), decyl (26), and alpha-naphthyryl (28) disulfides in a series of 6-TG (14) derivatives. These 6-TG derivatives were promising for antitumor agents.

Topics: Animals; Antineoplastic Agents; Disulfides; Mercaptopurine; Mice; Sarcoma 180; Structure-Activity Relationship; Thioguanine

Topics: 4-Nitrophenylphosphatase; Alkaline Phosphatase; Animals; Cell Membrane; Drug Resistance; Female; Mice; Nitrophenols; Sarcoma 180; Thioguanine

Topics: Animals; Cell Membrane; Concanavalin A; Depression, Chemical; Glycoproteins; Lectins; Mannose; Mice; Neoplasm Proteins; Ricin; Sarcoma 180; Thioguanine; Time Factors

A series of tetramisole derivatives was synthesized and tested for inhibitory activity against alkaline phosphatase which was partially purified from a murine ascitic neoplasm resistant to 6-thiopurines (Sarcoma 180/TG). These agents included derivatives substituted with halogens, CH3, or NO2 groups at either the meta or para position of the phenyl ring of tetramisole and 2,3-dehydrotetramisole. The phenyl ring of tetramisole and 2,3-dehydrotetramisole was also replaced by a naphthyl ring, and the phenyl ring of 2,3-dehydrotetramisole was substituted by a thienyl ring system. The presence of both the thiazolidine and dihydroimidazole rings of tetramisole was found to be essential for enzyme inhibitory activity. Substitution of a naphthyl for the phenyl group and dehydrogenation at the 2,3 position of the thiazolidine ring were found to significantly enhance inhibitory activity for alkaline phosphatase. Tests employing (S)-(-)-6-(4-bromophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole oxalate in combination with 6-thioguanine demonstrated that the inhibitor of alkaline phosphatase was capable of increasing the toxicity of 6-thioguanine to Sarcoma 180/TG cells in tissue culture.

Topics: Alkaline Phosphatase; Animals; Cells, Cultured; Cyclization; Drug Interactions; Drug Resistance; Purines; Sarcoma 180; Structure-Activity Relationship; Tetramisole; Thioguanine

Topics: Animals; Female; Fucose; Glycoproteins; Guanosine Diphosphate Fucose; In Vitro Techniques; Membrane Proteins; Mice; Neoplasm Proteins; Sarcoma 180; Thioguanine; Time Factors

Topics: Alkaline Phosphatase; Animals; Beryllium; Dose-Response Relationship, Drug; Heterocyclic Compounds; Imidazoles; Kinetics; Mice; Sarcoma 180; Semicarbazones; Structure-Activity Relationship; Tetramisole; Thiazoles; Thioguanine

Topics: Amino Acids; Animals; Ascites; Azaserine; Carbon Isotopes; Centrifugation, Density Gradient; Cytological Techniques; Dactinomycin; Leucine; Male; Mice; Mice, Inbred ICR; Microsomes; Neoplasm Proteins; Neoplasm Transplantation; RNA, Neoplasm; RNA, Ribosomal; RNA, Transfer; Sarcoma 180; Subcellular Fractions; Sulfur Isotopes; Thioguanine; Transplantation, Homologous; Tritium

Topics: Adenosine; Animals; Benzene Derivatives; Carcinoma 256, Walker; Cell Division; Cells, Cultured; Drug Synergism; Evaluation Studies as Topic; Leukemia L1210; Mercaptopurine; Mice; Mice, Inbred DBA; Rats; Sarcoma 180; Thioguanine

Topics: Animals; Azaserine; Cell Division; Cell Line; Cells, Cultured; Chromatography, Thin Layer; Drug Synergism; Female; Guanine Nucleotides; Guanosine Triphosphate; Half-Life; Mercaptopurine; Mice; Nucleosides; Nucleotides; Peritoneal Cavity; Ribonucleosides; Ribonucleotides; Sarcoma 180; Sulfur Isotopes; Thioguanine; Time Factors; Uracil Nucleotides

Topics: Adenosine Monophosphate; Adenosine Triphosphate; Animals; Azaguanine; Chromatography, DEAE-Cellulose; Electrophoresis; Erythrocytes; Female; Guanine Nucleotides; Humans; Inosine Nucleotides; Isoelectric Focusing; Isoenzymes; Kinetics; Mice; Mice, Inbred Strains; Molecular Weight; Phosphotransferases; Polysaccharides; Sarcoma 180; Structure-Activity Relationship; Thioguanine

Topics: Acid Phosphatase; Alkaline Phosphatase; Animals; Calcium; Cell Line; Cell-Free System; Drug Resistance; Female; Hydrogen-Ion Concentration; In Vitro Techniques; Magnesium; Mercaptopurine; Mice; Nucleotidases; Sarcoma 180; Subcellular Fractions; Thioguanine

Topics: Animals; Male; Mercaptopurine; Mice; Mice, Inbred Strains; Nucleosides; Ribonucleosides; Sarcoma 180; Sarcoma, Experimental; Thioguanine

Topics: Adenine; Adenocarcinoma; Animals; Azaserine; Carbon Isotopes; Cell Line; Feedback; Hypoxanthines; Mercaptopurine; Methotrexate; Neoplasms, Experimental; Nucleotides; Phosphotransferases; Purines; Sarcoma 180; Thioguanine

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Carcinoma, Ehrlich Tumor; Chemical Phenomena; Chemistry; Female; Formamides; Injections, Intraperitoneal; Leukemia, Experimental; Mice; Organ Size; Sarcoma 180; Thioguanine; Time Factors

Topics: Animals; Antimetabolites; Antineoplastic Agents; Chelating Agents; Chlorides; Copper; DNA, Neoplasm; Drug Synergism; Female; Fluorouracil; Hydrazines; Mice; Neoplasm Transplantation; RNA, Neoplasm; Sarcoma 180; Stearic Acids; Thioguanine; Thiosemicarbazones; Uracil Mustard

Topics: Adenosine Triphosphate; Animals; Azaguanine; Brain; Guanine Nucleotides; Kinetics; Nucleotides; Oxidoreductases; Phosphates; Phosphotransferases; Sarcoma 180; Swine; Thioguanine

Topics: Animals; Antineoplastic Agents; DNA, Neoplasm; Drug Synergism; Female; Fluorouracil; In Vitro Techniques; Leukemia L1210; Lysine; Male; Mice; Mitomycins; Mortality; Neoplasm Proteins; Neoplasm Transplantation; Orotic Acid; RNA, Neoplasm; Sarcoma 180; Thioguanine; Thymidine; Thymidine Kinase

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Chelating Agents; Cortisone; Leucine; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Rats; Research; Sarcoma 180; Streptomycin; Thioguanine; Transplantation

Topics: Animals; Antineoplastic Agents; Aspartic Acid; Azaguanine; Carbon Isotopes; Glycine; Guanine Nucleotides; Imidazoles; Liver; Lyases; Mercaptopurine; Metabolism; Mice; Neoplasms, Experimental; Nucleotides; Pharmacology; Purines; Research; Sarcoma 180; Thioguanine

Topics: Alkylating Agents; Animals; Antibody Formation; Antineoplastic Agents; Azaserine; Imidazoles; Mercaptopurine; Mice; Pharmacology; Purines; Rats; Research; Sarcoma 180; Tetanus Toxoid; Thioguanine; Toxicology

Topics: Adenine; Animals; Antimetabolites; Antineoplastic Agents; Cell Biology; DNA; DNA, Neoplasm; Guanine; Metabolism; Mice; Nucleotides; Pharmacology; Purines; Research; RNA; RNA, Neoplasm; Sarcoma 180; Thioguanine

Topics: Animals; Antineoplastic Agents; Carbon Isotopes; Cell Death; DNA; Injections, Intraperitoneal; Macromolecular Substances; Metabolism; Mice; Neoplasm Proteins; Nitrogen Mustard Compounds; Peritoneal Cavity; Pharmacology; Proteins; Radiometry; Research; RNA; Sarcoma 180; Thioguanine; Tritium; Uracil Mustard

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Mercaptopurine; Mice; Neoplasms; Neoplasms, Experimental; Research; Sarcoma 180; Thioguanine; Toxicology

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azaguanine; Azaserine; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; DNA; DNA, Neoplasm; Fluorouracil; Idoxuridine; Liver Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Mercaptopurine; Mice; Neoplasms, Experimental; Nitrogen Mustard Compounds; Nucleosides; Nucleotides; Purines; Research; RNA; RNA, Neoplasm; Sarcoma 180; Thioguanine; Uracil Mustard

Topics: Animals; Antineoplastic Agents; Ascites; Azaserine; Carbon Isotopes; DNA; DNA, Neoplasm; Glycine; Guanine; Lysine; Metabolism; Mice; Pharmacology; Proteins; Research; RNA; RNA, Neoplasm; Sarcoma 180; Thioguanine; Tissue Culture Techniques; Uracil

Combinations of 6-thioguanine and uracil mustard produced greater inhibition of the growth of sarcoma 180 than that equivalent to the sum of the inhibitory effects caused by the optimum levels of the individual drugs. This potentiation was accomplished without marked weight loss by the host. Some possible biochemical mechanisms responsible for the drug synergy are discussed.

Topics: Animals; Antineoplastic Agents; Mercaptopurine; Sarcoma 180; Thioguanine; Uracil; Uracil Mustard

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Leukemia L1210; Nucleosides; Research; Sarcoma 180; Thioguanine

Topics: Animals; Antineoplastic Agents; Azaserine; Glyceraldehyde; Humans; Purines; Sarcoma 180; Thioguanine