Investigation of HMN-176 anticancer activity in human tumor specimens in vitro and the effects of HMN-176 on differential gene expression.
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.
Medina-Gundrum
Leticia
L
Cancer Therapy and Research Center d/b/a The Institute for Drug Development, San Antonio, TX 78245-3217, USA.
Cerna
Cesario
C
Gomez
Lionel
L
Izbicka
Elzbieta
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003114:Colony-Forming Units Assay; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C479799:(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D014408:Biomarkers, Tumor; D011725:Pyridines