Parallel assessment of glutathione‐based detoxifying enzymes, O⁶‐alkylguanine‐dna alkyltransferase and P‐glycoprotein as indicators of drug resistance in tumor and normal lung of patients with lung cancer

Abstract

The levels of several potential indicators of drug resistance were measured in tumor and corresponding normal tissue of 55 untreated patients with lung cancer. The resistance parameters include glutathione (GSH) level, activities of the enzymes glutathione transferase (GST), glutathione peroxidase (GPx) and O6-alkylguanine-DNA alkyltransferase (ATase), as well as expression of P-glycoprotein (Pgp). Median values of GSH, GST and GPx were significantly higher in tumor than in normal tissue of non-small-cell lung cancer (NSCLC) or of small-cell lung cancer (SCLC), whereas ATase was elevated in tumor tissue of NSCLC only. Pgp expression as determined by Western blotting was significantly lower in tumor than in normal tissue of NSCLC. Resistance-parameter expression did not correlate with stage of disease or age of the patients. We found a negative correlation between smoking intensity and GSH level in normal tissue. Our findings indicate that the fundamental differences in chemosensitivity between SCLC and NSCLC cannot be explained by differences in the GSH-system or in the expression of Pgp. However, the level of ATase activity may be one of the factors responsible for the difference in chemosensitivity.

Immunohistochemical detection of DNA topoisomerase IIα, P-glycoprotein and multidrug resistance protein (MRP) in small-cell and non-small-cell lung cancer

“…In this respect, a mRNA and/or catalytic assay for topo-Ila should be more dependable as this protein is, for practical purposes, only found in tumour tissue. Both P-gp and MRP have been detected in SCLC and NSCLC, although their clinical importance is still undecided (Volm et al, 1991;Holzmayer et al, 1992;Segawa et al, 1993;Tabata et al, 1993;Abe et al, 1994;Oberli-Schrammli et al, 1994;Peoch et al, 1994;Thomas et al, 1994;Ota et al, 1995;Sugarawa et al, 1995;Beer et al, 1996;Chuman et al, 1996;Giaccone et al, 1996;Narasaki et al, 1996;Nooter et al, 1996;Stammler et al, 1996). In the present study, their incidence was equal in untreated SCLC and NSCLC (Tables 1 and 2), indicating that these drug efflux pumps are not themselves responsible for the very different sensitivities to etoposide in these two diseases.…”

Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues

“…Previous studies investigating cancer development have examined various genes, including oncogenes, tumor suppressor genes, DNA repair genes, and genes encoding phase I and II enzymes (9)(10)(11)(12). GSH levels have been shown to be elevated in numerous types of human cancer, including bone marrow (13), breast (14,15) and lung (16,17). Therefore, understanding the role of GSH in the development of cancer will be a significant step towards cancer prevention and/or attenuation.…”

Mechanism of Tracking and Cleavage of Adduct-damaged DNA Substrates by the Mammalian 5′- to 3′-Exonuclease/Endonuclease RAD2 Homologue 1 or Flap Endonuclease 1

“…Unfortunately, patients eventually develop resistance to this drug, which is often accompanied by resistance to other chemotherapeutic agents (22). Resistant cell lines have increased DNA repair capabilities (23,24). Recently, it has been suggested that deficiencies in DNA repair may result in an increased sensitivity of some tumors to CDDP (25).…”