Abstract
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 μg/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 μg/ml, 67% of non small-cell lung (4/6) and 57% of ovarian (4/7) cancer specimens treated with 10 μg/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 μg/ml. Evaluation of differential gene expression in drug-sensitive (A2780) and drug-resistant (A2780cp) ovarian carcinoma cell lines exposed to 0.1 μg/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.
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Takagi M, Honmura T, Watanabe S, Yamaguchi R, Nogawa M, Nishimura I, Katoh F, Matsuda M, Hidaka H: In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176. Invest New Drugs 21(4): 387-399, 2003
Tanaka H, Ohshima N, Ikenoya M, Komori K, Katoh F, Hidaka H: HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug resistant cells by targeting the transcription factor NF-Y. Cancer Res. 63(20): 6942-6947, 2003
Hamburger AW, Salmon SE: Primary bioassay of human tumor stem cells. Science 197: 461-463, 1977.
Von Hoff DD, Casper J, Bradley E, Sandbach J, Jones D, Makuch R: Association between human tumor colony forming assay results and response of an individual patient's tumor to chemotherapy. Am J Med 70: 1027-1041, 1981
Scheithauer W, Clark GM, Salmon SE, Dorda W, Shoemaker RH, Von Hoff DD: Model for estimation of clinically achievable plasma concentrations for investigational anticancer drugs in man. Cancer Treat Rep 70: 1379-1382, 1986
Hanauske U, Hanauske A-R, Marshall MH, Muggia VA, Von Hoff DD: Biphasic effects of vanadium salts on in vitro tumor colony growth. Int J Cell Cloning 5: 171-178, 1987
Von Hoff DD, Clark GM, Stogdill BJ, Sarodsy MF, O'Brien MT, Casper JT, Mattox DE, Page CP, Cruz AP, Sandbach JF: Prospective clinical trial of a human tumor cloning system. Cancer Res 43: 1926-1931, 1983
Shoemaker RH, Wolpert-Defillipes MK, Kern DH, Lieber MM, Makuch RW, Melnick NR, Miller WT, Salmon SE, Simon RM, Venditti JM, Von Hoff DD: Application of a human tumor colony forming assay to new drug screening. Cancer Res 45: 2145-2153, 1985
Browman GP, Levine MN, Robert RS: Editorial: Bench to bedside research and the human tumor stem-cell assay-bridging the credibility gap. J Clin Oncol 4: 1730-1731, 1986
Von Hoff DD: Human tumor stem cell assays. Int J Cell Cloning 5: 365-367, 1987
Hanauske AR, Degen D, Hilsenbeck SG, Bissery MC, Von Hoff DD: Effects of taxotere and taxol on in vitro colony formation of freshly explanted human tumor cells. Anti-Cancer Drugs 3: 121-124, 1992
Eckardt JR, Burris III HA, Kuhn JG, Bissery MC, Klink-Alakl M, Clark GM, Von Hoff DD: Activity of intoplicine (RP60475), a new DNAtopoisomerase I and II inhibitor, against human tumor colonyforming units in vitro. J Natl Cancer Inst 86 (1): 30-33, 1994
Raymond E, Hanauske A, Faivre S, Izbicka E, Clark G, Rowinsky EK, Von Hoff DD: Effects of prolonged versus short-term exposure paclitaxel (TaxolR )onhuman tumor colony-forming units. Anti-Cancer Drugs 8: 379-385, 1997
Hidalgo M, Izbicka E, Cerna C, Gomez L, Rowinsky EK, Weitman SD, Von Hoff DD: Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay. Anti-Cancer Drugs 10(3): 295-302, 1999
Diab SG, Hilsenbeck SG, Izbicka E, Weitman SD, Von Hoff DD: Significant activity of a novel cytotoxic agent, Ly295501, against a wide range of tumors in the human tumor cloning system. Anti-Cancer Drugs 10: 303-307, 1999
Petit T, Izbicka E, Lawrence RA, Bishop WR, Weitman SD, Von Hoff DD: Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. Ann Oncol 10: 449-453, 1999
Sakata K, Shigemasa K, Nagai N, Ohama K: Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. Int J Oncol 17(4): 673-681, 2000
Von Hoff, Daniel D: He's Not Going to Talk About In vitro Predictive Assays Again, Is He? JNCI 82(2): 96-101, 1990
Li YT, Shen F, Bai JY, Cheng GF: Inhibition of dexamethasone, indomethacin and resveratrol on matrix metalloproteinase-9 and the mechanism of inhibition. Yao Xue Xue Bao 38(7): 501-504, 2003
Liang Y, McDonnell S, Clynes M. Examining the relationship between cancer invasion/metastasis and drug resistance. Curr Cancer Drug Targets 2(3): 257-277, 2002
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Medina-Gundrum, L., Cerna, C., Gomez, L. et al. Investigation of HMN-176 anticancer activity in human tumor specimens in vitro and the effects of HMN-176 on differential gene expression. Invest New Drugs 23, 3–9 (2005). https://doi.org/10.1023/B:DRUG.0000047100.64540.f6
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DOI: https://doi.org/10.1023/B:DRUG.0000047100.64540.f6