1-arabinofuranosylcytosine-5--stearylphosphate and Leukemia-P388

We investigated the antitumor effect of oral administration of etoposide and arabinofuranosylcytosine-5'-stearylphosphate (C18PCA) against P388 ascites tumors in B6D2F1 mice. Etoposide (25 mg/kg) and C18PCA (5 mg/kg) were given orally on days 1-5 after tumor inoculation. The median life span of the mice treated with etoposide or C18PCA alone was 19.5 and 18 days, respectively. The combination of both drugs significantly extended the median life span to 33 days. To clarify this enhancement of the increase in median life span, we examined intracellular deoxyribonucleoside triphosphate (dNTP) pools, cell-cycle distribution, DNA fragmentation, and the time course of the plasma drug concentration. Etoposide had no effect on intracellular dNTP pools in this experimental system, whereas treatment of cells with C18PCA or with the combination of both drugs resulted in a significant increase in dTTP pools to values ranging from 1.8- to 2.0-fold higher than the control levels. There was a significant increase in cells in the S + G2/M phase when cells had been treated with both etoposide and C18PCA. Agarose-gel electrophoresis of the extracted DNA revealed that C18PCA enhanced the fragmentation of DNA, with a length of about 180 bp being induced by etoposide. The plasma peak levels of etoposide (1000 nM) and ara-C (50 nM) were observed at 20 and 30 min after the simultaneous administration of both drugs, respectively. The plasma etoposide level gradually decreased to 10% of the peak level at 240 min after administration. On the other hand, the plasma concentration of ara-C was maintained at above 20 nM at 240 min. These observations suggest that C18PCA and etoposide act on P388 murine leukemic cells by accumulating cells in the S + G2/M phase. Even if the plasma concentration of ara-C is low, the repair of DNA damage by etoposide may be hindered in the presence of ara-C following an increase in DNA fragmentation.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Etoposide; Leukemia P388; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Time Factors; Treatment Outcome

Combined activity of 4-amino-1-beta-D-arabinofuranosyl-2(1H)-pyrimidinone 5'-(sodium octadecyl phosphate) monohydrate, YNK01, with other antitumor agents was studied with mouse P388 and L1210 leukemia in vivo. The two-drug combinations with doxorubicin, daunorubicin, mitomycin C, cisplatin or vincristine showed marked synergistic effects against P388 leukemia. However, YNK01 plus methotrexate showed additive or competitive effect. Among these combinations, the combination with doxorubicin showed greatest activity and the number of cured mice were observed in a wide dose range. In a three-drug combination with daunorubicin and 6-mercaptopurine against L1210 leukemia, the combined effect was more synergistic than two-drug combinations with each of the three drugs. From these results, YNK 01 is expected to be a useful agent in combination chemotherapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cisplatin; Cytidine Monophosphate; Cytosine Nucleotides; Daunorubicin; Doxorubicin; Drug Synergism; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mercaptopurine; Mice; Mice, Inbred DBA; Mitomycin; Mitomycins; Vincristine

1-B-D-arabinofuranosylcytosine-5'-stearylphosphate (C18PCA), which is an Ara-CMP ester and one of the most promising orally effective anti-leukemic drugs, is a newly synthesized derivative of Ara-C. The antitumor effect of C18PCA and Ara-C was investigated against the P388 ascites tumor in BDF1 mice. Treatment with C18PCA (100 mg kg-1, orally) and Ara-C (40 mg kg-1, subcutaneously) was administered on days 1, 3 and 5 after tumor inoculation. The percentage increase in lifespans of the mice treated with C18PCA or Ara-C were 84.4% and 53.9%, respectively. The determination of the plasma Ara-C concentration revealed that the plasma concentration of Ara-C was retained much longer in mice which orally received C18PCA than in those which received Ara-C. By using high-performance liquid chromatography, it was revealed that the deoxyribonucleoside triphosphate pools increased gradually but Ara-CTP concentration once increased, then decreased rapidly when Ara-C was administered subcutaneously. On the other hand, both the intracellular deoxyribonucleoside triphosphate (dNTP) pools and Ara-CTP level increased gradually after oral administration of C18PCA. We concluded that these longer-term biochemical effects, even if the plasma concentration of Ara-C and Ara-CTP level were low, might be correlated with antitumor effects of C18PCA.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arabinofuranosylcytosine Triphosphate; Arabinonucleotides; Chromatography, High Pressure Liquid; Cytarabine; Cytidine Monophosphate; Deoxyribonucleotides; Leukemia P388; Male; Mice