Deoxycytidine protects normal bone marrow progenitors against Ara-C and gemcitabine cytotoxicity without compromising their activity against cisplatin-resistant human ovarian cancer cells.
The intracellular metabolism and cytotoxic effects of Ara-C and 2'-difluorodeoxycytidine (dFdC or Gemcitabine) administered with or without deoxycytidine (dCyd) were examined in cisplatin-resistant (2008/C13) and -sensitive (2008) human ovarian cystadenocarcinoma cells. Compared to 2008 cells, 2008/C13 cells possess 2.1-fold higher glutathione (GSH) levels, enhanced expressions of GSH S-transferase (GST)-pi mRNA and protein, and significantly greater activity of GST, GSH peroxidase, and GST reductase. Although 2008/C13 cells were slightly cross-resistant to 4-hydroperoxycyclophosphamide, the drug displayed a steep dose-response (colony growth inhibition) effect toward these cells. 2008/C13 cells expressed greater sensitivity toward Ara-C and Gemcitabine. This was associated with intracellular Ara-CTP and dFdCtriphosphate levels in 2008/C13 significantly higher than those in 2008 cells. Against bone marrow progenitor cells, the cytotoxic effects of submicromolar levels of Ara-C or dFdC, produced in plasma following intraperitoneal administration of the drugs, were significantly reversed by cotreatment with high levels of dCyd achieved in plasma following intravenous administration. In contrast, the metabolism and cytotoxic effects of Ara-C and dFdC in 2008 and 2008/C13 cells were not significantly altered by dCyd concentrations that are reached in the peritoneum following intravenous administration. These in vitro data suggest that systematically administered dCyd might protect bone marrow progenitor cells against Ara-C cytotoxicity without impairing antitumor activity of intraperitoneal Ara-C.
Bhalla
K
K
Department of Medicine, Medical University of South Carolina, Charleston 29425.
Holladay
C
C
Lutzky
J
J
Ibrado
A M
AM
Bullock
G
G
Jasiok
M
M
Singh
S
S
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D015153:Blotting, Western; D001854:Bone Marrow Cells; D002945:Cisplatin / Q000627:therapeutic use*; D003536:Cystadenocarcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000032:analysis / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D003561:Cytarabine; D003841:Deoxycytidine; D005982:Glutathione Transferase; D002945:Cisplatin; D000093542:Gemcitabine