thioguanine-anhydrous and Carcinoma--Squamous-Cell

Cancer appears to be a disease of altered maturation, with changes in genetic expression leading to a situation in which the physiological regulation of cellular proliferation and maturation are altered. Environmental factors as well as defined chemical agents have been demonstrated to have the capacity to convert neoplastic cells to end-stage forms with a finite life span through a process characteristic of cellular maturation. The correction of genetic defects by these inducers of differentiation does not appear to be required; the critical feature is that the differentiated cells assume a state in which they no longer possess the capability for continued cellular replication. The extrapolation of these advances, accomplished in experimental systems, to clinical practice should yield significant decreases in the neoplastic cell burden without the degree of morbidity produced by aggressive therapy with cytodestructive agents, especially when employed in multidrug combinations. The ultimate introduction of differentiation as a therapeutic approach to cancer treatment if attained, however, will require a variety of principles to be established, so that optimum efficacy may be obtained from each agent, the fabrication of new agents with major changes in the ratio of the concentrations required to produce cytotoxicity relative to those necessary to initiate maturation is attained, and the elucidation of non-antagonistic combinations of differentiation inducing agents with or without cytotoxic drugs is achieved to combat the problem of tumor cell heterogeneity.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Humans; Hydrocortisone; Leukemia, Experimental; Models, Biological; Naphthacenes; Phenotype; Thioguanine; Tretinoin

Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Differentiation; Cell Division; Cell Line; Cell Survival; Cell Transformation, Neoplastic; Epidermal Growth Factor; Humans; Leukemia, Myeloid; Models, Biological; Naphthacenes; Thioguanine; Tretinoin

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Bleomycin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Humans; Lung Neoplasms; Methotrexate; Mitomycins; Nitrosourea Compounds; Thioguanine; Vinblastine; Vincristine

Fifteen patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck received a 5 day continuous I.V. infusion of 6-thioguanine repeated every five weeks. Dose limiting toxicity was primarily hematological with grade III/IV leucopenia and thrombocytopenia seen in seven patients. Nausea and vomiting was moderate and well controlled with antiemetics. No complete or partial responses were observed, with a median time to progression of 58 days and a median survival of 227+ days for the entire group. Based on these results we do not recommend I.V. 6-thioguanine for the treatment of this disease.

Topics: Adult; Aged; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Thioguanine; Treatment Outcome

Topics: Azathioprine; Carcinoma, Squamous Cell; DNA Damage; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Mutagenesis; Oxidative Stress; Radiography; Risk Factors; Skin; Skin Neoplasms; Thioguanine; Ultraviolet Rays

Topics: Animals; Bleomycin; Carcinoma, Squamous Cell; Chlorocebus aethiops; Drug Resistance; Fibroblasts; Fluorescent Antibody Technique; Fluorouracil; Humans; Methotrexate; Mice; Mutation; Simplexvirus; Thioguanine; Uridine

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Cyclophosphamide; Drug Therapy, Combination; Fluorouracil; Heparin; Humans; Infusions, Parenteral; Lung Neoplasms; Male; Methotrexate; Middle Aged; Thioguanine; Vincristine

The effects of 6-thioguanine on purine biosynthesis and cell viability have been examined in H.Ep. 2 cells grown in culture. Toxicity is not reversed by aminoimidazolecarboxamide, suggesting that inhibition of purine biosynthesis de novo is not the sole mechanism of toxicity. Also, 6-(methylmercapto)purine ribonucleoside, a potent inhibitor of purine biosynthesis de novo, produces more marked reductions in cellular pools of purines than does 6-thioguanine without killing cells. There is no apparent inhibition by 6-thioguanosine 5'-monophosphate of other enzymes leading to the synthesis of guanosine 5'-triphosphate as determined in whole cells by measurements of radioactive hypoxanthine or guanine incorporation. Inhibition of DNA synthesis by 1 mM thymidine protects cells from 6-mercaptopurine or 6-thioguanine but fails to protect cells from 8-azaguanine toxicity. On the other hand, inhibition of RNA synthesis by 6-azauridine plus deoxycytidine protects cells against 8-azaguanine but does not protect against 6-thioguanine or 6-mercaptopurine toxicity. In agreement with the in vitro data, arabinosylcytosine (a potent inhibitor of DNA synthesis) fails to protect mice against 8-azaguanine but has previously been shown to protect mice from 6-mercaptopurine or 6-thioguanine toxicity. The results support the hypotheses of others that incorporation into DNA (as 6-thioguanine nucleotide) is a mechanism of toxicity for these thiopurines, whereas 8-azaguanine is toxic due to its incorporation into RNA.

Topics: Azaguanine; Azauridine; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Cytarabine; Deoxycytidine; DNA, Neoplasm; Guanine; Hypoxanthines; Imidazoles; Mercaptopurine; Methylthioinosine; Purines; RNA, Neoplasm; Thioguanine; Thymidine

Topics: Animals; Carcinoma, Squamous Cell; Cell Line; Deoxyribonucleosides; DNA, Neoplasm; Drug Resistance; Guanine; Humans; Hypoxanthines; Leukemia L1210; Mercaptopurine; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neoplasms, Experimental; Pentosyltransferases; Thioguanine

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

Topics: Autoradiography; Carbon Isotopes; Carcinoma, Squamous Cell; Cell Line; Chemical Phenomena; Chemistry; Chromatography, Thin Layer; Electrophoresis; Guanine Nucleotides; Humans; Hydrolysis; Mercaptopurine; Metabolism; Methionine; Methylation; Paper; Pentosephosphates; Phosphoric Acids; Phosphoric Monoester Hydrolases; Purines; Ribonucleotides; Ribose; Sulfides; Sulfur; Sulfur Isotopes; Thioguanine; Transferases; Venoms

Topics: Adenine; Animals; Antimetabolites; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Glycine; Hypoxanthines; Imidazoles; Leukemia L1210; Mercaptopurine; Nucleotides; Pharmacology; Purines; Research; Ribonucleotides; Thioguanine; Tissue Culture Techniques; Xanthines

Topics: Adult; Aged; Antimetabolites; Azo Compounds; Carcinoma, Squamous Cell; Drug Synergism; Female; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Lung Neoplasms; Male; Maxillary Neoplasms; Middle Aged; Mouth Neoplasms; Nasopharyngeal Neoplasms; Pancreatic Neoplasms; Pharyngeal Neoplasms; Sulfur Isotopes; Thioguanine; Tongue Neoplasms; Tonsillar Neoplasms

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: Adenocarcinoma; Alopecia; Antineoplastic Agents; Azaserine; Carcinoma, Squamous Cell; Diarrhea; Drug Eruptions; Drug Therapy; Geriatrics; Guanine; Leukopenia; Nausea; Neoplasms; Stomatitis; Thioguanine; Thrombocytopenia; Toxicology