PubMed · 7964972
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R T Dorr, D Lauper. 1994. Dosing error in protocol book.. https://doi.org/10.1200/jco.1994.12.11.2520
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Molecular studies have revealed that microsatellite instability and loss of heterozygosity occurred in head-and-neck cancer, suggesting the involvement both of suppressor and of mutator pathways in head-and-neck carcinogenesis. There is evidence for relations between tumor phenotype and clinical parameters. Indeed, replication-error phenotype, characterized by microsatellite instability, was associated with decreased sensitivity to chemotherapeutic agents in cell lines. Loss of heterozygosity is a frequent mechanism of inactivation of tumor-suppressor genes, which might be implicated in resistance to chemotherapy. In head-and-neck cancer, chemosensitivity is inconstant, and no marker is available to predict response to treatment. In order to evaluate the role of tumor phenotype on resistance to chemotherapy, we analyzed 56 primary head-and-neck squamous-cell carcinomas collected at time of diagnosis and a sub-group of 23 resistant tumors collected after chemotherapy at 22 microsatellite loci. At time of diagnosis, only one tumor showed MSI-H phenotype. Loss of heterozygosity (LOH) was observed in 75% of tumors, indicating the dominant role of the suppressor in comparison with the mutator pathway in HNSCC carcinogenesis. No change in microsatellite patterns was observed after treatment, suggesting that chemotherapy did not select mismatch-repair-deficient clones. Univariate analyses showed that LOH at 9p or 17p was significantly associated with drug resistance. In a multivariate analysis, only LOH at 17p remains predictive of low response to chemotherapy, with a relative risk of 3.7 and 95% CI of 1.1-13, indicating that p53 alterations could play a role in chemotherapy resistance in HNSCC. Int. J. Cancer (Pred. Oncol.) 84:410-415, 1999.
Glutathione (gamma-glutamylcysteinyl glycine, GSH) is believed to be important in the acquisition of resistance to anti-cancer drugs such as cisplatin (CDDP) and doxorubicin (DOX). gamma-Glutamylcysteine synthetase (gamma-GCS) is a key enzyme for maintaining intracellular GSH levels; it is composed of a catalytic heavy (gamma-GCSh) and a regulatory light (gamma-GCSl) sub-unit. In the present study, the expression of gamma-GCS sub-units was examined in human cancer cell lines. The levels of GSH, the expression of gamma-GCSh and gamma-GCSl mRNAs and proteins in human cancer cells were higher in CDDP-resistant cells and DOX-resistant cells than in the drug-sensitive cells. Treatment of CDDP/DOX-resistant human colonic-cancer cells (HCT8DDP) with CDDP and DOX caused simultaneous induction of the expression of gamma-GCSh and gamma-GCSl mRNAs. The transcriptional regulation of gamma-GCS was studied and it was observed that the DNA-binding activity of activator protein 1 (AP-1) is induced by CDDP and DOX using an electrophoretic mobility shift assay. We constructed chimeric genes containing various regions of the gamma-GCSh-promoter gene and the coding region for luciferase. The HCT8DDP cells transiently transfected with a plasmid containing an AP-1 site of the gamma-GCSh-promoter-luciferase construct showed increased luciferase activity when treated with CDDP and DOX. These results suggest that stimulation of the expression of gamma-GCSh by CDDP and DOX is mediated by AP-1, which relates to the resistance of cancer cells to the drug.
We have analyzed paraffin sections from 190 patients with histologically confirmed Hodgkin's disease (HD) for the presence of Epstein-Barr virus (EBV) using in situ hybridization to detect the EBV-encoded Epstein-Barr virus early RNAs (EBERs) and immunohistochemistry to identify latent membrane protein-1 (LMP1) expression. EBV was present in the tumor cells in 51 HD cases (27%) and was mainly confined to the mixed cellularity and nodular sclerosis subtypes. There was no difference between EBV-positive and EBV-negative HD patients with regard to age, clinical stage, presentation, and the number of alternating chemotherapy cycles of ChIVPP and PABIOE received. The complete remission rate after study chemotherapy was 80% in EBV-positive patients versus 69% in EBV-negative patients (P =.05). The 2-year failure-free survival rate was significantly better for EBV-positive patients when compared with the EBV-negative HD group (P =.02). Although 2-year and 5-year overall survival rates were better for EBV-positive HD patients, the differences were not statistically significant (P =.18 and P =.40, respectively). In conclusion, the results confirm the favorable prognostic value of EBV in the tumor cells of HD patients and suggest important differences in response to chemotherapy between EBV-positive and EBV-negative patients.