thioguanine-anhydrous and Lung-Neoplasms

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

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

Nineteen eligible patients with recurrent small cell lung cancer were treated with a 120 hour continuous infusion of 6-thioguanine at a starting dose of 35 mg/m2/day. There were no responses in these 19 patients. Toxicity was acceptable with the primary toxicity being hematologic. Based on this trial, 6-thioguanine is not felt to have significant antitumor activity in this patient population.

Topics: Aged; Carcinoma, Small Cell; Drugs, Investigational; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Thioguanine; Time Factors

This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Thioguanine

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Thioguanine

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

Topics: A549 Cells; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Female; Humans; Immunotherapy; Lung Neoplasms; Mice; Mice, Inbred BALB C; Molecular Structure; Neoplasms, Experimental; Phosphoric Diester Hydrolases; Pyrophosphatases; Small Molecule Libraries; Structure-Activity Relationship; Thioguanine

PET list-mode data were collected for each subject and DDG software was utilized for extracting respiratory waveforms. PET images was reconstructed using Q.clear and Q.clear + DDG, respectively. We evaluated SUVmax, SUVmean, the coefficient of variance (CoV), metabolic tumor volume (MTV), and tumor heterogeneity using the area under the curve of cumulative SUV histogram (AUC-CSH). Metabolic parameter changes were compared between each reconstruction method. The Deep-Expiration Breath Hold (DEBH) protocol was introduced for CT scans to correct spatial misalignment between PET and CT and compared with conventional free breathing. The DEBH and free breathing (FB) protocol comparison was made in a separate matching cohort using propensity core matching rather than the same patient.. Total 147 PET/CT scans with excessive respiratory movements were used to study DDG-mediated correction. After DDG application, SUVmax (P < 0.0001; 8.15 ± 4.77 vs. 9.03 ± 5.02) and SUVmean (P < 0.0001; 4.91 ± 2.44 vs. 5.49 ± 2.68) of lung and upper abdomen lesions increased, while MTV significantly decreased (P < 0.0001; 7.07 ± 15.46 vs. 6.58 ± 15.14). In addition, the percent change of SUVs was greater in lower lung lesions compared to upper lobe lesions. Likewise, the MTV reduction was significantly greater in lower lobe lesions. No significant difference dependent on location was observed in liver lesions. DEBH-mediated CT breathing correction did not make a significant difference in lesion metabolic parameters compared to conventional free breathing.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fluorodeoxyglucose F18; Humans; Image Processing, Computer-Assisted; Lung; Lung Neoplasms; Movement; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Respiratory-Gated Imaging Techniques; Thioguanine; Tumor Burden

This study aimed to find whether antioxidants increase or decrease the effect of chemotherapeutic drug in the in vitro model.. Small lung Cancer cell line (A549) was treated with anticancer drug 6-Thioguanine (6-TG) at different concentration viz., 1, 10, 50 and 100μM and the proliferation was measured using MTT assay. The antioxidant N-Acetyl Cysteine (NAC) in different ratios viz., 1mM, 5mM and 10mM were assayed for their effect in proliferation on the A549 cells alone and in combination with 6-TG.. Our experiment proves that anticancer drug 6-TG decreases the proliferation and the antioxidant NAC enhances the proliferation of A549 cells. Strikingly when co-treated with 6-TG, the antioxidant NAC diminished the proliferation reduction action of 6-TG on A549 cells.. Our results suggest that antioxidants in fact benefit the tumor cell growth when treated alone and when in combination with anticancer drug, it severely impair the activity of the drug. We propose that extreme care should be taken when prescribing antioxidants alone or in combination with chemotherapeutics.

Topics: Acetylcysteine; Antimetabolites, Antineoplastic; Antioxidants; Apoptosis; Cell Proliferation; Drug Therapy, Combination; Free Radical Scavengers; Humans; Lung Neoplasms; Thioguanine; Tumor Cells, Cultured

To demonstrate the feasibility of fast Dual-Source CT (DSCT) and to evaluate the clinical utility in chest/abdomen/pelvis staging CT studies.. 45 cancer patients with two follow-up combined chest/abdomen/pelvis staging CT examinations (maximally ±10 kV difference in tube potential) were included. The first scan had to be performed with our standard protocol (fixed pitch 0.6), the second one using a novel fast-speed DSCT protocol (fixed pitch 1.55). Effective doses (ED) were calculated, noise measurements performed. Scan times were compared, motion artefacts and the diagnostic confidence rated in consensus reading.. ED for the standard and fast-speed scans was 9.1 (7.0-11.1) mSv and 9.2 (7.4-12.8) mSv, respectively (P = 0.075). Image noise was comparable (abdomen; all P > 0.05) or reduced for fast-speed CTs (trachea, P = 0.001; ascending aorta, P < 0.001). Motion artefacts of the heart/the ascending aorta (all P < 0.001) and breathing artefacts (P < 0.031) were reduced in fast DSCT. The diagnostic confidence for the evaluation of mediastinal (P < 0.001) and pulmonary (P = 0.008) pathologies was improved for fast DSCT.. Fast DSCT for chest/abdomen/pelvis staging CT examinations is performed within 2 seconds scan time and eliminates relevant intrathoracic motion/breathing artefacts. Mediastinal/pulmonary pathologies can thus be assessed with high diagnostic confidence. Abdominal image quality remains excellent.. • Fast dual-source CT provides chest/abdomen/pelvis staging examinations within 2 seconds scan time. • The sevenfold scan time reduction eliminates relevant intrathoracic motion/breathing artefacts. • Mediastinal/pulmonary pathologies can now be assessed with high diagnostic confidence. • The coverage of the peripheral soft tissues is comparable to single-source CT. • Fast and large-volume oncologic DSCT can be performed with 9 mSv effective dose.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Feasibility Studies; Female; Humans; Lung Neoplasms; Male; Mediastinum; Middle Aged; Neoplasms; Pelvis; Radiation Dosage; Radiography, Abdominal; Radiography, Thoracic; Retrospective Studies; Thioguanine; Thoracic Neoplasms; Tomography, X-Ray Computed

The structure-activity relationship studies of ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (1, HA 14-1), an antagonist of the antiapoptotic Bcl-2 proteins, are reported. A series of analogues of 1 with varied functional groups at the 6-position of the chromene ring were synthesized. These candidates were evaluated for their binding interactions with three antiapoptotic proteins: Bcl-2, Bcl-XL, and Bcl-w. They were also assayed for their in vitro cytotoxicities against a set of Jurkat cells with varied levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). It was found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodate a variety of alkyl groups. 1 and its analogues bind to all of the three antiapoptotic Bcl-2 proteins tested. Positive correlations were observed between the binding affinities of these candidates to the antiapoptotic Bcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely to be the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small molecules to antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptide binding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, were obtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most active compound, 3g, had a >3-fold increase of binding affinity to the antiapoptotic Bcl-2 proteins and a >13-fold increase of in vitro cytotoxicity over 1. Though Jurkat cells with transgenic overexpression of Bcl-2 or Bcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistance to 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that 1 and its analogues function as antagonists for antiapoptotic Bcl-2 proteins and that they have the potential, either as a single agent or as a combination therapy with other anticancer agents, to treat cancers with the overexpression of antiapoptotic Bcl-2 proteins.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Benzopyrans; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Jurkat Cells; Lung Neoplasms; Nitriles; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Tumor Cells, Cultured

By screening 1,990 compounds from the National Cancer Institute diversity set library against human topoisomerase IIalpha, we identified a novel catalytic topoisomerase II inhibitor NSC35866, a S6-substituted analogue of thioguanine. In addition to inhibiting the DNA strand passage reaction of human topoisomerase IIalpha, NSC35866 also inhibited its ATPase reaction. NSC35866 primarily inhibited DNA-stimulated ATPase activity, whereas DNA-independent ATPase activity was less sensitive to inhibition. We compared the mode of topoisomerase II ATPase inhibition induced by NSC35866 with that of 12 other substituted purine analogues of different chemical classes. The ability of thiopurines with free SH functionalities to inhibit topoisomerase II ATPase activity was completely abolished by DTT, suggesting that these thiopurines inhibit topoisomerase II ATPase activity by covalently modifying free cysteine residues. In contrast, NSC35866 as well as two O6-substituted guanine analogues, O6-benzylguanine and NU2058, could inhibit topoisomerase II ATPase activity in the presence of DTT, indicating that they have a different mechanism of inhibition. NSC35866 did not increase the level of topoisomerase II covalent cleavable complexes with DNA, indicating that it is a catalytic inhibitor and not a poison. NSC35866 was also capable of inducing a salt-stable complex of topoisomerase II on closed circular DNA. In accordance with these biochemical data, NSC35866 could antagonize etoposide-induced cytotoxicity and DNA breaks in human and murine cancer cells, confirming that NSC35866 also functions as a catalytic topoisomerase II inhibitor in cells.

Topics: Antigens, Neoplasm; Carcinoma, Small Cell; Catalysis; Cell Line, Tumor; DNA Topoisomerases, Type II; DNA-Binding Proteins; DNA, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Histones; Humans; Lung Neoplasms; Nocodazole; Phosphorylation; Purines; Thioguanine; Topoisomerase II Inhibitors

We report on a 49 year old female with primary extra-medullary manifestation of a acute myeloid leukemia in the lungs without leukemic signs. The disease was diagnosed by detection of leukemic blast cells in bronchoalveolar lavage. Chemotherapy with the TAD-VP-scheme resulted in partial remission. The patient died in systemic early relapse. To our knowledge this is the first description of primary isolated extra-medullary manifestation of a acute myeloid leukemia in the lungs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bronchoalveolar Lavage Fluid; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Middle Aged; Prednisolone; Radiography; Thioguanine; Vincristine

Direct pulmonary instillation of 1,6-dinitropyrene (DNP) into male Fischer 344 rats results in a dose-dependent induction of lung tumors and 6-thioguanine-resistant (TGr) T-lymphocytes. The treatment also results in DNP binding to dG in the lung and in T-lymphocytes. In the present study, we have examined the types of mutations associated with these responses to DNP. Sequencing of DNA amplification products from 20 DNP-induced lung tumors identified 5 mutations in K-ras codon 12, 4 GGT-->TGT transversions and one GGT-->GAT transition. No mutations were found in K-ras codons 13 or 61. Single-strand conformation polymorphism analysis of p53 exons 5-8 revealed mobility shifts indicative of mutation in 9 of the 20 tumor samples. Eight of the mutations were substitutions at G:C base pairs, and one was a deletion of a single G:C base pair. DNA from 161 TGr lymphocyte colonies cultured from DNP-treated rats was examined for point mutations by amplification of hprt exons 2, 3, and 8, and screening the products for mutant: wild-type heteroduplex formation by denaturing gradient-gel electrophoresis. Only three mutations were found, a G-->T transversion in exon 3, a G-->A transition in exon 8, and a complex mutation consisting of a tandem G-->T transversion and a one base deletion in exon 3. The mutations identified in the DNP-induced lung tumors and TGr T-lymphocytes are consistent with the formation of dG-DNA adducts by DNP. The extremely low recovery of point mutations from TGr lymphocytes suggests that DNP induces a substantial number of mutations by other mechanisms.

Topics: Animals; Clone Cells; DNA Mutational Analysis; Drug Resistance; Exons; Genes, p53; Genes, ras; Hypoxanthine Phosphoribosyltransferase; Lung Neoplasms; Male; Mutagens; Point Mutation; Pyrenes; Rats; Rats, Inbred F344; T-Lymphocytes; Thioguanine

Human peripheral blood lymphocytes (PBL) were selected for 6-thioguanine (6-TG) resistance in short-term (42-h) cultures in 110 high-cancer-risk industrial workers, 131 primary lung cancer patients and 96 low-risk controls. The lymphocytes were cultured and stimulated by phytohemagglutinin (PHA). A labeling index (LI) was scored using light microscope autoradiography, based on the lymphocyte's ability to incorporate tritiated thymidine with or without selective agent 6-TG. The number of 6-TG-resistant cells increased in the high-occupational-cancer-risk group of vinyl chloride- and mixed organic industrial dust (MOID)-exposed workers as well as in the primary lung cancer patients. The results were compared with the low-occupational-cancer-risk groups and with samples taken from the 70 healthy individuals and 26 hospitalized, non-cancerous controls. In both risk-exposed groups the frequency of 6-TG-resistant lymphocytes was significantly higher (p less than 0.01) than in the controls. These results suggest that the original Strauss and Albertini (1977, 1979) method can be used to study qualitative risk assessment in carcinogen- or mutagen-exposed occupational groups.

Topics: Carcinogens; Drug Resistance; Humans; Hypoxanthine Phosphoribosyltransferase; In Vitro Techniques; Lung Neoplasms; Lymphocyte Activation; Lymphocytes; Mutagens; Occupational Diseases; Thioguanine

Antitumor activities of a combination chemotherapy with a water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), and a single dose of 6-thioguanine were studied using three obstinate murine tumor systems, i.e., Lewis lung carcinoma, B16 melanoma, and an advanced stage of L1210 leukemia systems. Therapeutically synergistic effect was observed either definitely against 1- or 2-day-old Lewis lung carcinoma and 6-day-old L1210 leukemia or moderately against 1-day-old B16 melanoma. Single intravenous treatment on day 7 after subcutaneous implantation of Lewis lung carcinoma, when the tumors had already metastasized to the lungs, produced a significant regression of tumor and a significant increment in survival time of tumor-bearing mice. In comparative studies, the combination of ACNU and 6-thioguanine showed a greater and a wider spectrum of antitumor activities against these tumors than those obtained by the combination with ACNU and a single dose of 5-fluorouracil, methotrexate, or 6-mercaptopurine. Increment in lethal toxicity for normal and tumor-bearing mice was not observed by the combination of ACNU and 6-thioguanine in contrast to definite increases in this toxicity by the combination of ACNU and 5-fluorouracil. The present experimental results may suggest the clinical utility of the combination chemotherapy with ACNU and 6-thioguanine in the treatment of several solid tumors as well as acute leukemias.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Drug Synergism; Drug Therapy, Combination; Female; Injections, Intraperitoneal; Injections, Intravenous; Leukemia L1210; Lung Neoplasms; Male; Melanoma; Mercaptopurine; Mice; Neoplasms, Experimental; Nimustine; Nitrosourea Compounds; Thioguanine

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

Twenty-eight patients with inoperable or metastatic carcinoma of the lung who failed to respond to conventional chemotherapy and/or radiotherapy were entered in this study. All of them received repeated courses of multiple chemotherapy (cyclophosphamide, 5-fluorouracil, 6-thioguanine, methotrexate, and vincristine) with or without concurrent intravenous heparin anticoagulation. No tumor regression was noted in any of the 14 patients who received the multiple chemotherapy only. On the contrary, tumor progression was seen in all of them, and subsequently 12 died of their disease. The other 14 patients were anticoagulated with heparin, then received the same multiple chemotherapeutics while anticoagulated. Over 50% tumor regression was noted clinically and radiologically, and occasionally demonstrated histologically in 7 of them. Two patients in this group are alive and well for 1 1/2 years. No increase in toxicity or metastases was noted. The 2 patients who had progression of their disease while on the multiple chemotherapy program alone showed tumor regression when they received the same chemotherapy after heparinization.

Topics: Adult; Aged; Cyclophosphamide; Drug Tolerance; Female; Fluorouracil; Heparin; Humans; Lung Neoplasms; Male; Methotrexate; Middle Aged; 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

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