hmn-176 and Neoplasms

HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose.. Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1.. A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted.. The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).

Topics: Administration, Oral; Adult; Aged; Benzylidene Compounds; Cell Cycle Proteins; Cohort Studies; Cyclic N-Oxides; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Middle Aged; Molecular Structure; Neoplasms; Polo-Like Kinase 1; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Pyridines; Stilbenes; Structure-Activity Relationship; Sulfonamides; Treatment Outcome

HMN-176, (E)-4-(2-[2-(N-[4-methoxybenzene-sulfonyl]amino)phenyl]ethenyl) pyridine 1-oxide, is a stilbene derivative which inhibits mitosis without significant effect on tubulin polymerization and displays potent cytotoxicity against a variety of human tumor cell lines. The present study evaluated the activity profile of the antineoplastic agent HMN-176 in an ex-vivo soft agar cloning assay (human tumor colony-forming assay) in a panel of 132 human tumor specimens under 14-day continuous exposure at 0.1, 1.0, and 10.0 microg/ml. Thirty percent of specimens in the different treatment groups (39/132 in 0.1 and 1.0 test groups; 40/132 in 10.0 test group) were assessable, falling within the negative and positive control parameters. At these dose levels, responses were observed in 32% (11/34), 62% (21/34), and 71% (25/35) of assessable specimens, respectively. HMN-176 demonstrated activity towards 75% of the breast cancer specimens (6/8) treated with 1.0 microg/ml, 67% of non small-cell lung (4/6) and 57% of ovarian (4/7) cancer specimens treated with 10 microg/ml. Low levels of cross-resistance to cisplatin, cyclophosphamide, 5-fluorouracil, and etoposide were also observed. There was a positive relationship between HMN-176 concentration and effect, demonstrating greatest overall activity at 10.0 microg/ml. Evaluation of differential gene expression in drug-sensitive (A2780) and drug-resistant (A2780cp) ovarian carcinoma cell lines exposed to 0.1 microg/ml HMN-176 up to 48 h using cDNA microarrays with 1,154 known human genes revealed significant drug effects on tumor associated genes, including upregulation of tissue inhibitor matrix metalloproteinases gene (TIMP) in both cell lines, suggesting that HMN-176 could potentially overcome tumor drug resistance. In conclusion, in vitro responses demonstrate efficacy at pharmacologically relevant concentrations, which suggests that HMN-176 deserves further evaluation in clinical trials.

Topics: Antineoplastic Agents; Benzylidene Compounds; Biomarkers, Tumor; Colony-Forming Units Assay; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Neoplasms; Oligonucleotide Array Sequence Analysis; Pyridines; Tumor Cells, Cultured