Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian cancer.
OBJECTIVE
The objective was to assess the relationship between glutathione content and drug sensitivity with glutathione modulation in ovarian cancer in a pilot study using 31 samples of freshly obtained ovarian tumor material from 26 patients with advanced disease.


METHODS
Processed tumor samples were screened to determine the glutathione content using an enzyme recycling assay modified for use in a 96-well plate format. Chemosensitivity testing (MTT assay) was used to assess sensitivity to cisplatin and doxorubicin and modulation using buthionine sulfoximine. Multidrug-resistance-associated protein MRP1 (putative drug-glutathione conjugate transporter) expression was also assessed.


RESULTS
There was a significant increase in the tumor cell GSH levels in samples from patients who had received previous chemotherapy (9) versus those from chemotherapy-naïve patients (20), P = 0.005. In vitro chemosensitivity testing with doxorubicin and cisplatin (using LC(50) values, i.e., drug dose causing 50% reduction in cell survival relative to untreated control) failed to show a relationship with glutathione levels. Coincubation of cisplatin and doxorubicin with buthionine sulfoximine resulted in a significant increase in sensitivity to both of these drugs overall (cisplatin, P = 0.05; doxorubicin, P = 0.025), with 20 samples showing sensitization to a drug to which they were previously resistant. MRP1 expression failed to show a correlation with drug sensitivity and glutathione levels.


CONCLUSIONS
Our study supports the use of glutathione modulation using agents such as buthionine sulfoximine in patients with heavily pretreated, drug-resistant ovarian cancer.
Lewandowicz
Grazyna M
GM
Haematology Research, Pembury Hospital, Pembury, Tunbridge Wells, Kent TN2 4QJ, United Kingdom.
Britt
Paul
P
Elgie
Alena W
AW
Williamson
Christine J
CJ
Coley
Helen M
HM
Hall
Andrew G
AG
Sargent
Jean M
JM
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010865:Pilot Projects; D011379:Prognosis; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D019328:Buthionine Sulfoximine; D002945:Cisplatin; D004317:Doxorubicin; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1