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Deoxycytidine protects normal bone marrow progenitors against Ara-C and gemcitabine cytotoxicity without compromising their activity against cisplatin-resistant human ovarian cancer cells. 1992

K Bhalla, and C Holladay, and J Lutzky, and A M Ibrado, and G Bullock, and M Jasiok, and S Singh
Department of Medicine, Medical University of South Carolina, Charleston 29425.

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.

UI MeSH Term Description Entries
D007274 Injections, Intraperitoneal Forceful administration into the peritoneal cavity of liquid medication, nutrient, or other fluid through a hollow needle piercing the abdominal wall. Intraperitoneal Injections,Injection, Intraperitoneal,Intraperitoneal Injection
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D010051 Ovarian Neoplasms Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS. Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D001854 Bone Marrow Cells Cells contained in the bone marrow including fat cells (see ADIPOCYTES); STROMAL CELLS; MEGAKARYOCYTES; and the immediate precursors of most blood cells. Bone Marrow Cell,Cell, Bone Marrow,Cells, Bone Marrow,Marrow Cell, Bone,Marrow Cells, Bone
D002945 Cisplatin An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. Platinum Diamminodichloride,cis-Diamminedichloroplatinum(II),cis-Dichlorodiammineplatinum(II),Biocisplatinum,Dichlorodiammineplatinum,NSC-119875,Platidiam,Platino,Platinol,cis-Diamminedichloroplatinum,cis-Platinum,Diamminodichloride, Platinum,cis Diamminedichloroplatinum,cis Platinum
D003536 Cystadenocarcinoma A malignant neoplasm derived from glandular epithelium, in which cystic accumulations of retained secretions are formed. The neoplastic cells manifest varying degrees of anaplasia and invasiveness, and local extension and metastases occur. Cystadenocarcinomas develop frequently in the ovaries, where pseudomucinous and serous types are recognized. (Stedman, 25th ed) Cystadenocarcinomas
D003561 Cytarabine A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472) Ara-C,Arabinofuranosylcytosine,Arabinosylcytosine,Cytosine Arabinoside,Aracytidine,Aracytine,Cytarabine Hydrochloride,Cytonal,Cytosar,Cytosar-U,beta-Ara C,Ara C,Arabinoside, Cytosine,Cytosar U,beta Ara C
D003841 Deoxycytidine A nucleoside component of DNA composed of CYTOSINE and DEOXYRIBOSE. Cytosine Deoxyribonucleoside,Cytosine Deoxyriboside,Deoxyribonucleoside, Cytosine,Deoxyriboside, Cytosine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005260 Female Females

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