5--oleoyl-cytarabine and laromustine

For the last twenty years, significant progress in Molecular and Cellular Biology has resulted in a better characterization and understanding of the biology and prognosis of acute myeloid leukemia (AML). These achievements have provided new opportunities for the development of innovative, more effective therapies. Novel agents potentially useful in the treatment of patients with AML include new formulations of established drugs, newer nucleoside analogs, molecular target drugs, monoclonal antibodies and other agents. Three newer nucleoside analogs, clofarabine, troxacitabine and sapacitabine have been recently investigated in patients with AML. Two methylation inhibitors, 5-azacyticline and decitabine are pyrimidine nucleoside analogs of cytidine which can be incorporated into RNA and/or DNA. Lower doses of these agents are active in AML and have been extensively investigated, especially in secondary AML and AML in elderly patients. Tipifarnib and lonafarnib are orally available farnesyltransferase inhibitors with in vitro and in vivo activity against AML. In recent years, FLT3 inhibitors, lestaurinib, tandutinib and PKC 412 have been developed and tested in AML. The preclinical observations and clinical studies indicate that FLT3 inhibitors are promising agents in the treatment of FLT3 mutated AML patients, especially when used in combinations with chemotherapy. Several newer MDR inhibitors, including valspodar (PSC-833) and zosuquidar trihydrochloride have been also tested for the treatment of relapsed AML. This article reviews the various classes of AML targets and drugs that are under early phase clinical evaluation, especially those that are likely to enter clinical practice in the near future.

Topics: Adenine Nucleotides; Animals; Arabinonucleosides; Azacitidine; Benzamides; Clofarabine; Cytarabine; Cytosine; Daunorubicin; Decitabine; Dioxolanes; Farnesyltranstransferase; Histone Deacetylase Inhibitors; Humans; Hydrazines; Imatinib Mesylate; Leukemia, Myeloid, Acute; Liposomes; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; TOR Serine-Threonine Kinases; Valproic Acid; Vascular Endothelial Growth Factor Receptor-1

This study evaluated combination drug partners for CP-4055, the C18:1(Delta9,trans) unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition was assessed by ATP assay and drug interaction by the combination index and three dimensional methods. Synergy was observed in HL-60 cells for simultaneous combinations of CP-4055 with gemcitabine, irinotecan and topotecan, while combinations with cloretazine (VNP40101M) and idarubicin were additive. In U937 cells, synergy was observed with gemcitabine and additivity for the other drugs. In HL-60, the IC50 concentration of CP-4055 could be reduced 10-fold and that of gemcitabine 3-fold in combination versus the agents alone, an interaction that was independent of drug sequence, ratio and exposure time. In contrast, interactions of CP-4055 with the topoisomerase inhibitors became antagonistic when the drugs were administered 24 h prior to CP-4055 and at certain drug ratios, particularly in U937 cells. In summary, CP-4055 produced additive to synergistic anti proliferative activity when combined simultaneously with drugs from four mechanistic classes in cell culture models of human leukemia and lymphoma. The impact of drug sequence and ratio on the interactions argues for incorporation of these parameters into the design of combination chemotherapy regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Cytarabine; Deoxycytidine; Drug Interactions; Drug Screening Assays, Antitumor; Gemcitabine; Humans; Hydrazines; Idarubicin; Irinotecan; Leukemia; Lymphoma; Sulfonamides; Topotecan