Me. Richardson et Dw. Siemann, THIOL-RELATED MECHANISMS OF RESISTANCE IN A MURINE TUMOR-MODEL, International journal of radiation oncology, biology, physics, 29(2), 1994, pp. 387-392
Citations number
25
Categorie Soggetti
Oncology,"Radiology,Nuclear Medicine & Medical Imaging
Purpose: The aim of these studies was to provide evidence supporting t
hiol-related alterations as a mechanism of resistance in the cyclophos
phamide (CP)-resistant subline, KHT-rcp/iv, and to elucidate the mecha
nism by which the observed elevation in GSH is achieved. Methods and M
aterials: The response of the parental and resistant cells to three an
ticancer agents (adriamycin, cisplatin, and ionizing radiation), previ
ously associated with thiol-related resistance, was determined using a
clonogenic cell survival assay. Further, using spectrophotometric tec
hniques, the activities of several glutathione (GSH)related enzymes; g
lutathione S-transferase (GST), glutathione peroxidase (GSH-PX), gluta
thione reductase (GSR), gamma-glutamylcysteine synthetase (GCS) and ga
mma-glutamyl transpeptidase (GGT) were also measured. Results: The stu
dies indicated that the CP-resistant cells were cross-resistant to adr
iamycin, cisplatin and ionizing radiation. In addition, the KHT-rcp/iv
cells exhibited 2-3-fold increases in GST, GSR and GCS activity. Sinc
e GCS catalyzes the rate-limiting step of GSH synthesis, increased act
ivity of this enzyme may be one mechanism by which intracellular GSH l
evels may be upregulated in treatment refractory tumor cells. No signi
ficant difference in GSH-PX activity was observed between the two cell
lines, while GGT activity could not be detected in either cell line.
Conclusion: Taken together, these results suggest that thiols could pl
ay a significant role in the acquired resistance and cross-resistance
to chemotherapeutic agents. Modulation of these enzymes may be an effe
ctive means of enhancing anticancer therapies.