thioguanine-anhydrous and Pancreatic-Neoplasms

In a phase II study, 32 patients with advanced pancreatic carcinoma were treated with intravenous 6-thioguanine. A 30-min infusion of 55 mg/m2 (starting dose) was administered once a day for 5 consecutive days, the course being repeated every 5 weeks. A median of two courses (range, 1-10) was administered. Among the 32 patients, 30 having measurable cancer and optimum follow-up were fully assessable for response. One patient achieved a partial response of extensive liver metastases (12+ months), and another patient had a transient minor response (5 weeks). Cancer in 27 of 30 assessable patients progressed during intravenous 6-thioguanine treatment. Myelosuppression, although frequent, was mild to moderate at these doses and did not result in significant morbidity. Nonhematologic toxicities were also mild. Our data suggest that intravenous 6-thioguanine given at this schedule is ineffective in previously untreated patients with advanced carcinoma of the pancreas.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Pancreatic Neoplasms; Thioguanine

Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed an IC

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Drug Evaluation, Preclinical; Gemcitabine; Humans; MAP Kinase Signaling System; Methyltransferases; Pancreatic Neoplasms; Proto-Oncogene Proteins B-raf; Signal Transduction; Thioguanine; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Pancreatic adenocarcinoma is one of the malignancies that is highly resistant to therapy and among the leading causes of cancer-related death. Several factors may influence pancreatic cancer resistance, and expression of ATP-binding cassette transport proteins is one of the major mechanisms of drug resistance. Members of this family's C-branch, also referred to as multidrug resistance-associated proteins (MRPs), might be of particular interest because they are able to efflux nucleoside analogs used in the treatment of pancreatic cancer. Expression of MRP1, MRP3, MRP4, and MRP5 in human pancreas and pancreatic carcinoma has been reported. However, contributions of MRPs to chemoresistance of pancreatic cancer are not fully understood. MRP5 mRNA expression in pancreatic adenocarcinoma cell lines correlated significantly with cellular sensitivity to 5-fluorouracil (5-FU) (r = 0.738, p < 0.05). Long-term treatment with 5-FU increased expression of MRP5 by 2.4-fold and was associated with significant drug resistance [IC(50) values for control and 5-fluorouracil (5-FU)-resistant Patu-T cell lines were 11.3 ± 5.3 and 33.2 ± 6.9 μM, respectively (p < 0.05)]. Consequently, overexpression of MRP5 in Colo-357 cells resulted in significantly reduced accumulation of 5-FU related radioactivity and 5-FU cytotoxicity. Knockdown of MRP5 significantly increased cellular cytotoxicity of 5-FU to Patu-02 cells and enhanced accumulation of radioactivity related to 5-FU and its metabolites. Our results suggest that MRP5 is expressed and functionally active and contributes to variable sensitivities of pancreatic adenocarcinoma cell lines to 5-FU. Further investigations using models that resemble human pancreas tumors are necessary to prove a causative relation between expression and activity of MRP5 and tumor resistance to 5-FU.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fluorouracil; Gene Knockdown Techniques; Humans; Multidrug Resistance-Associated Proteins; Pancreas; Pancreatic Neoplasms; RNA; RNA Interference; Tumor Cells, Cultured

PANC02 is a unique experimental animal tumor that fails to respond significantly to any known clinically active antitumor agent. In this regard, the murine ductal adenocarcinoma resembles its human counterpart. To study the mechanism for its intrinsic resistance to 6-thioguanine (TG), we compared the metabolism of the drug in PANC02 and a reference, TG-sensitive adenocarcinoma, CA-755. In comparison with CA-755, PANC02 cells were approximately 6 times less sensitive to TG and CHO cells were 80 times less sensitive in tissue culture. Nevertheless, the incorporation of TG into the DNA of these three cell lines was approximately equal at the lowest concentrations capable of reducing cloning efficiency by 50%, i.e., 3.0-3.8 pmol (dthioGMP)/nmol (dGMP). In mice bearing bilateral implants of CA-755 and PANC02, only CA-755 responded to TG treatment. At various doses used on various schedules, the incorporation of TG into CA-755 DNA readily achieved that observed to be cytotoxic to the cells in vitro, whereas the incorporation into the DNA of PANC02 tumor cells did not. Although the biochemical basis for the poor incorporation of TG into the DNA of PANC02 in vivo is not known, this factor appears to explain the refractoriness of PANC02 as compared with CA-755 to this antitumor antimetabolite.

Topics: Adenocarcinoma; Animals; Cell Division; Drug Resistance; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Pancreatic Neoplasms; Thioguanine

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