xk-469 and Neoplasms

To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose.. R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies.. Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma.. The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Quinoxalines; Treatment Outcome

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.

Topics: Aldehyde Oxidase; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Cohort Studies; Genetic Variation; Genotype; Humans; Liver; Neoplasms; Pharmacogenetics; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Quinoxalines

XK469 (2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid), a synthetic quinoxaline phenoxypropionic acid derivative, has broad activity against murine tumors and is entering Phase I clinical development as a topoisomerase IIbeta inhibitor. This study investigated the underlying molecular mechanism of XK469's effects on the cell cycle.. Growth inhibition, cell cycle arrest, induction of p53 and p21 mRNA and protein, and cdc2 phosphorylation and kinase activity were studied in treated cells from the H460 lung cancer line and p21 and p53 knockout cells of the HCT 116 colon cancer line.. XK469 arrested H460 cells at G(2)-M, which was associated with cdc2 phosphorylation and decreased cdc2 kinase activity. Moreover, XK469 stabilized p53 and subsequently increased p21(WAF1/CIP1). Furthermore, HCT116 p21(-/-) cells were less sensitive than wild-type cells to XK469-induced growth inhibition, but p53(+/+) and p53(-/-) cells were equally sensitive despite the absence of p21 induction in the p53(-/-) cells.. When considered with published data, our study suggests a complex mechanism of XK469-mediated anticancer activity involving multiple pathways, including p53-dependent and -independent G(2)-M arrest via inactivation of cdc2-cyclin B1 kinase activity.

Topics: Antineoplastic Agents; Cell Cycle; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Dose-Response Relationship, Drug; G2 Phase; Gene Expression Regulation, Neoplastic; Humans; Mitosis; Mutation; Neoplasms; Quinoxalines; RNA, Messenger; Tumor Cells, Cultured; Tumor Suppressor Protein p53