Cytosine Drugs

Cytarabine, 4-amino-l-/3-D-arabinofuranosylpyrimidin-2(lif)-one or cytosine arabino-side (1033 R = H, X = NH2), is an established drug for the treatment of acute leukaemias of childhood and adult granulocytic leukaemia. It must be given intravenously and much of the drug becomes the corresponding inactive uracil derivative in vivo by virtue of a deaminase in the liver it interferes with DNA but not RNA synthesis, and it has incidental... 

Intraperitoneal administration of chemotherapeutic agents has been used for many years as a way of increasing the delivery of drugs to tumors (e.g., ovarian carcinoma) located in the peritoneal cavity (Markman, 1986 Howell and Zimra, 1988). Cisplatin (Casper et al., 1983 Markman et al., 1985), cytosine arabinoside (Ara-C) (King et al., 1984 Markman et al., 1985, 1986), and bleomycin (Markman et al., 1986) are examples of intraperitoneally administered drugs which were already successfully applied in clinical settings. 

Hunt, C. A., Rustum, Y. M., Mayhew, E., and Papahadjopoulos, D. (1979). Retention of cytosine arabinoside in mouse lung following intravenous administration in liposomes of different size, Drug Metabol. Dispos., 7, 124-128. 

Juliano, R. L., and Me Cullough, H. N. (1980). Controlled delivery of an antitumor drug Localized action of liposome encapsulated cytosine arabinoside administered via the respiratory system, J. Pharmacol. Exp. Ther., 214, 381-387. 

Mayhew, E., Rustum, Y. M., and Szoka, F. (1982). Therapeutic efficacy of cytosine arabinoside trapped in liposomes, in Targeting of Drugs (G. Gregoriadis, J. Senior, and A. TTOuet, eds.). Plenum Press, New York, pp. 249-260. 

Albumin. Albumin is available in highly pure and uniform form, and exhibits low toxicity and good biological stability. It has been used as a carrier for methotrexate and a variety of antiviral drugs [amantadine, fioxuridine (5-fluorodeoxyuridine), and cytar-abine (cytosine arabinoside)] to treat macrophage tumors and infections caused by DNA viruses growing in macrophages. Heavily modified albumins are known... 

As well as NONOates, other NO donors also showed anticancer activity independently. Sodium nitroprusside (SNP), a metal-NO complex, showed cytotoxic effects on the cells of some patients with malignant lymphoma (ML), acute myelocytic leukemia (AML) or chronic myelomonocytic leukemia (CMMoL), but not with multiple myeloma [109]. SNP and cytosine arabinoside (Ara-C) did not share the drug resistance. Interestingly, SNP had no effect on lymphocytes of healthy volunteers. These results suggest that SNP has an anti-tumor effect on human hematological malignant cells. 

There has been some concern expressed regarding the use of CSFs to treat MDS patients. Because these cytokines have proliferative activity, they have the potential to induce a leukaemic transformation in the malignant clone. However, the combined use of CSFs with cytotoxic drugs such as cytosine arabinoside (ara-C) appears promising. If leukaemic clones are induced to proliferate by the cytokine, then they are killed by ara-C as they enter the cell cycle. Other forms of differentiation therapy, such as treatment with retinoids, 1,25-dihydroxyvitamin D3 and interferons, have also been tested, but results have been variable. 

Synthesis of Lipophilic Arabinofuranosyl Cytosine N" -Alkyl Derivatives and Heterodinucleoside Phosphate Duplex Drugs... 

Figure 2 In vitro cytotoxic activity on B16F1 melanoma cells of the duplex drugs in liposome formulations and of ETC dissolved in phosphate buffered saline. The corresponding IC50 values in mM are shown on the bars. Abbreviations ara-C-NOAC, arabinocytidylyl-N" -octadecyl-l-P-D-arabinofuranosylcytosine 5-FdU-NOAC, 2 -deoxy-5-fluorouridylyl-N" -octadecyl-l -P-D-arabinofuranosylcytosine ETC, ethynylcy-tidine [l-(3-C-ethynyl-P-D-ribopentafuranosyl)-cytosine] NOAC, ISf-octadecyl-ara-C PBS, phosphate buffered saline.

Cytosine arabinoside (araC) is used as an effective chemotherapeutic agent for cancer, although resistance to this drug may eventually develop. In certain cases, resistance is related to an increase in the enzyme cytidine deaminase in the tumor cells. This enzyme would inactivate araC to form... 

Cytarabine is an effective antimetabolite in treating leukemia. Like other pyrimidine antimetabolites, cytarabine must be activated by initially transforming into the corresponding nucleotide. The active form of the drag is cytarabine triphosphate. Cytarabine is used for all types of leukemia. Synonyms of this drug are cytosine, arabinoside, and ara-C. 

Mithramycin (also known as MIT and plicamy-cin) is an antibiotic that binds to DNA to regulate transcription. It attaches to specific regions of DNA that are rich in guanine and cytosine. It appears to lower serum calcium concentrations by blocking the hypercalcemic action of Vitamin D. After IV administration about 25% of the drug is excreted in the urine after 2 hours, and 40% after 15 hours. The main indications are treatment of testicular tumors and control of hypercalcemia and hypercalciuria. 

L D. Lamivudine, a cytosine analogue, is a nucleoside reverse transcriptase inhibitor that acts as a competitive inhibitor of reverse transcriptase. Efavirenz is a nonnucleoside reverse transcriptase inhibitor it acts by binding to a site adjacent to the enzyme s active site. Neither drug exhibits significant activity against HIV protease. 

Cytarabine (cytosine arabinoside, ara-C, Cytosar-U) is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine. It is one of the most active agents available for the treatment of acute myelogenous leukemia. Cytarabine kills cells in the S-phase of the cycle by competitively inhibiting DNA polymerase. The drug must... 

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