Incorporation into leukemia

The cytotoxic activities of the 2, 2 -difluoro analog (775) of 737 against Chinese hamster ovary and tumor cells, in comparison with those of 1- -d-arabinofuranosylcytosine ara-C, a drug for leukemia), have been studied 775 is transported the faster through membrane into cells, more effectively phosphorylated by the deoxycytidine kinase (to the 5 -mono-phosphate) and, after conversion into the 5 -triphosphate, more highly accumulated in the cells, with longer duration time, than is ara-C, but nevertheless 775 is incorporated into the DNA to a lesser extent than is ara-C. These characteristics of 775 were discussed. 

Rubas W, et al. Treatment of murine L1210 leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes. Int J Cancer 1986 37 149. 

The effect of 6-mercaptopurine on the incorporation of a number of C-labelled compounds into soluble purine nucleotides and into RNA and DNA has been studied in leukemia L1210, Ehrlich ascites carcinoma, and solid sarcoma 180. At a level of 6-mercaptopurine that markedly inhibited the incorporation of formate and glycine, the utilization of adenine or 2-aminoadenine was not affected. There was no inhibition of the incorporation of 5(or 4)-aminoimidazole-4(5)-carboxamide (AIC) into adenine derivatives and no marked or consistent inhibition of its incorporation into guanine derivatives. The conversion of AIC to purines in ascites cells was not inhibited at levels of 6-mercaptopurine 8-20 times those that produced 50 per cent or greater inhibition of de novo synthesis [292]. Furthermore, AIC reverses the inhibition of growth of S180 cells (AH/5) in culture by 6-mercaptopurine [293]. These results suggest that in all these systems, in vitro and in vivo, the principal site at which 6-mercaptopurine inhibits nucleic acid biosynthesis is prior to the formation of AIC, and that the interconversion of purine ribonucleotides (see below) is not the primary site of action [292]. Presumably, this early step is the conversion of PRPP to 5-phosphoribosylamine inhibited allosterically by 6-mercaptopurine ribonucleotide (feedback inhibition is not observed in cells that cannot convert 6-mercaptopurine to its ribonucleotide [244]. 

Cladribine, or 2-chlorodeoxyadenosine, is resistant to adenosine deaminase and after intracellular phosphorylation by deoxycytidine kinase, it is incorporated into DNA. It is considered the drug of choice in hairy cell leukemia because of high activity combined with acceptable toxicity. Cladribine shows variable oral absorbtion and is usually administered intravenously. Its concentration-time course is biphasic with plasma half-lives of 35 minutes and 6.7 hours. Excretion is primarily by the kidneys. Its most prominent dose-limiting toxicity is myelosup-pression. 

The product of this reaction, 6-TGMP, can eventually be converted to deoxy-6-thioguanosine-triphos-phate (dTGTP), which has been shown to be incorporated into DNA. Resistance of human leukemia cells to thioguanine has been correlated with decreased activity of HGPRTase and to increased inactivation of the thio nucleotides by alkaline phosphatase. 

Lecithin-based o/w MEs for parenteral use were formulated using polysorbate 80, IPM (Isopropyl myristate), lecithin, and water at different lecithin-polysorbate 80 weight ratios [115]. The formulated systems were shown to be highly stable and of minimal toxicity when evaluated in vitro. Phospholipid-based ME formulations of all-trans retinoic acid (ATRA) for parenteral administration were prepared and tested in vitro [116]. ATRA is effective against acute promyelocytic leukemia with highly variable oral bioavailability. Parenteral ME of ATRA was prepared using pharmaceutically acceptable ingredients, namely phospholipids and soybean oil. The inhibitory effect of ATRA on two human cancer cell lines (HL-60 and MCF-7) was not affected by incorporation into a ME formulation. 

Fig. 3. The gplSO family of cytokines and receptors. Schematic representation of gpl30 and leukemia inhibitory factor receptor (LIFR) oriented in a cell membrane. Of the four-helix bundle gplSO cytokines, structural information currently exists for human interleukin 6 (IL-6) (green) (Somers et al, 1997), human herpes virus interleukin 6 (HlTV-8 IL-6) (purple) (Chow et al, 2001a), ciliary neurotrophic factor (CNTF) (orange) (McDonald et al., 1995), leukemia inhibitory factor (LIF) (blue) (Robinson et al, 1994), and oncostatin-M (OSM) (red) (Deller et al, 2000). Lower panel is a detailed list of gplSO cytokines and the associated receptors incorporated into the final signaling complex. (See Color Insert.)...

Genetics has already been incorporated into the care of children with cancer an example is the Philadelphia Chromosome, a chromosomal anomaly produced as a result of reciprocal translocation between chromosomes 9 and 22 [t(9 22)(q34 qll)] that is most commonly seen as a marker of chronic myeloid leukemia [50]. The presence of this chromosomal anomaly is associated with altered prognosis—and the need for different therapy—when seen in the context of acute lymphoblastic leukemia in childhood [51], An area of oncology care where genetics has not been widely used has been in the evaluation—and possibly prevention—of adverse drug reactions [52],... 

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