oxadiazoles and Carcinoma--Squamous-Cell

A total of forty-three compounds were synthesized, including thirty-two new ones. Among those compounds, seventeen were selected and tested on human tumor cell lines: PC-3 (prostate adenocarcinoma), HCT-116 (colorectal tumor), NCIH-460 (lung carcinoma), SKMEL-103 (melanoma) and AGP-01 (gastric tumor). Alkynylated 1,2,4-oxadiazoles 2m, 3g and 3k exhibited antiproliferative activities against NCIH-460 in culture. Alkynylated N-cyclohexyl-1,2,4-oxadiazoles 3a-m and bis-heterocycle glucoglycero-1,2,3-triazole-N-cyclohexyl-1,2,4-oxadiazole derivatives 5a-k and 6-11 were evaluated for their in vitro efficacy towards Mycobacterium tuberculosis (Mtb) H

Topics: Alkynes; Animals; Antineoplastic Agents; Antitubercular Agents; Carcinoma, Squamous Cell; Cell Line; Cell Proliferation; Cell Survival; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Discovery; Glycoconjugates; Humans; Lung Neoplasms; Mice; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Oxadiazoles; Structure-Activity Relationship; Triazoles

The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy.. When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations.. BAY-87-2243 markedly decreased nuclear HIF-1α expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control.. Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Carcinoma, Squamous Cell; Cell Hypoxia; Chemoradiotherapy; Dose Fractionation, Radiation; Head and Neck Neoplasms; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Mice, Nude; Oxadiazoles; Pyrazoles; Radiation-Sensitizing Agents; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays

Carcinogenicity of eight 5-nitrofurans with heterocyclic substituents at the 2-position of the furan ring was investigated by feeding the chemicals to Sprague-Dawley female rats. N-[5-(5-nitro-2-furyl)-1,3,4-thiadiazol-2-yl]acetamide induced in 30 rats the highest incidence of tumors with the greatest number of tissues involved: forestomach squamous cell tumors (22), kidney pelvis transitional cell carcinomas (15), pulmonary alveolar cell carcinomas (16), hemangioendothelialsarcomas (20) of the intestine, mesentery, liver, lung, and pancreas, and a few tumors of other tissues. 2-Amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole, 2-amino-5-(5-nitro-2furyl)-1,3,4-oxadiazole, and trans-2-[dimethylamino)methylimino]-5-[2-(5-nitro-2-furyl)vinyl]-1,3,4-oxadiazole produced high incidences of mammary tumors. The other four 5-nitrofurans tested: N-[4-(5-NITRO-2-FURYL)-2-THIAZOLYL]ACETAMIDE;2,3,4-TRIFLUORO-N-[4-(5-NITRO-2-furyl)-2-thiazoly]acetamide;5-(5-nitro-2-furyl)-1,3,4-oxadiazol-2-ol; and N-( [3-(5-nitro-2-furyl)-1,2,4-oxadiazol-5-yl]methyl)acetamide were associated with tumor incidences of 40-60%. Two other chemicals were also tested: 2-Amino-5-nitrothiazole caused a low incidence of breast and kidney pelvis tumors, and 2-amino-4-(p-nitrophenyl)thiazole induced a high incidence of breast and salivary gland adenocarcinomas and lymphomas.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Administration, Oral; Amines; Animals; Carcinogens; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Female; Hemangiosarcoma; Intestinal Neoplasms; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphoma; Mammary Neoplasms, Experimental; Mesentery; Neoplasms, Experimental; Nitrofurans; Oxadiazoles; Pancreatic Neoplasms; Rats; Salivary Gland Neoplasms; Stomach Neoplasms; Thiadiazoles

Topics: Animals; Carcinogens; Carcinoma; Carcinoma, Squamous Cell; Dogs; Neoplasms; Neoplasms, Experimental; Oxadiazoles; Pathology; Rats; Research; Toxicology; Urinary Bladder Neoplasms