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.