Abstract
Aim:
The aim of this study was to creatively implement a novel chemo-gene-virotherapeutic strategy and further strengthen the antitumor effect in cancer cells by the combined use of ZD55-IL-24 and cisplatin.
Methods:
ZD55-IL-24 is an oncolytic adenovirus that harbors interleukin 24 (IL-24), which has a strong antitumor effect and was identified and evaluated by PCR, RT-PCR, and Western blot analysis. Enhancement of cancer cell death using a combination of ZD55-IL-24 and cisplatin was assessed in several cancer cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cytopathic effect (CPE) assay. Apoptosis induction by treatment with ZD55-IL-24 and/or cisplatin was detected in BEL7404 and SMMC7721 by morphological evaluation, apoptotic cell staining, and flow cytometry analysis. In addition, negative effects on normal cells were evaluated in the L-02 cell line using the MTT assay, the CPE assay, morphological evaluation, apoptotic cell staining, and flow cytometry analysis.
Results:
The combination of ZD55-IL-24 and cisplatin, which is superior to ZD55-IL-24, cisplatin, and ZD55-EGFP, as well as ZD55-EGFP plus cisplatin, resulted in a significantly increased effect. Most importantly, conjugation of ZD55-IL-24 with cisplatin had toxic effects equal to that of cisplatin and did not have overlapping toxicities in normal cells.
Conclusion:
This study showed that ZD55-IL-24 conjugated with cisplatin exhibited a remarkably increased cytotoxic and apoptosis-inducing effect in cancer cells and significantly reduced the toxicity in normal cells through the use of a reduced dose.
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References
Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB . Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995; 11: 2477–86.
Lebedeva IV, Su ZZ, Chang Y, Kitada S, Reed JC, Fisher PB . The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells. Oncogene 2002; 21: 708–18.
Su Z, Lebedeva IV, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, et al. A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc Natl Acad Sci USA 2001; 98: 10332–7.
Fisher PB, Gopalkrishnan RV, Chada S, Ramesh R, Grimm EA, Rosenfeld MR, et al. mda-7/IL-24, a novel cancer selective apoptosis inducing cytokine gene: from the laboratory into the clinic. Cancer Biol Ther 2003; 2: S23–S37.
Chada S, Mhashilkar AM, Liu Y, Nishikawa T, Bocangel D, Zheng M, et al. mda-7 gene transfer sensitizes breast carcinoma cells to chemotherapy, biologic therapies and radiotherapy: correlation with expression of bcl-2 family members. Cancer Gene Ther 2006; 13: 490–502.
Miyahara R, Banerjee S, Kawano K, Efferson C, Tsuda N, Miyahara Y, et al. Melanoma differentiation-associated gene-7 (mda-7)/interleukin (IL)-24 induces anticancer immunity in a syngeneic murine model. Cancer Gene Ther 2006; 13: 753–61.
Nishikawa T, Ramesh R, Munshi A, Chada S, Meyn RE . Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation. Mol Ther 2004; 9: 818–28
Chada S, Nemunaitis J, Tong A, Zhang Y, Su D, Mhashilkar A, et al. A Phase I dose-escalation study of Ad-mda7 (INGN 241) in patients with advanced carcinoma. Cancer Gene Ther 2001; 8 (Suppl 2): S3.
Chada S, Cunningham C, Zhang Y, Su D, Mhashilkar A, Ekmekcioglu S, et al. INGN 241 (Ad-mda-7) induces widespread apoptosis and activates the immune system in patients with advanced cancer. Mol Ther 2003; 7: S446.
Zhang ZL, Zou WG, Luo CX, Li BH, Wang JH, Sun LY, et al. An armed oncolytic adenovirus system, ZD55-gene, demonstrating potent antitumoral efficacy. Cell Res 2003; 13: 481–99.
Liu XY, Qiu SB, Zou WG, Pei ZF, Gu JF, Luo CX, et al. Effective gene-virotherapy for complete eradication of tumor mediated by the combination of htrail (tnfsf10) and plasminogen k5. Mol Therapy 2005; 11: 531–41.
Zhao L, Gu J, Dong A, Zhang Y, Zhong L, He L, et al. Potent antitumor activity of oncolytic adenovirus expressing mda-7/IL-24 for colorectal cancer. Hum Gene Ther 2005; 16: 845–58.
Kelland L . The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 2007; 7: 573–84.
Rosenberg B, Vancamp L, Krigas T . Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature 1965; 205: 698–9.
Morton RP, Rugman F, Dorman EB, Stoney PJ, Wilson JA, McCormick M, et al. Cisplatinum and bleomycin for advanced or recurrent squamous cell carcinoma of the head and neck: a randomized factorial phase III controlled trial. Cancer Chemother Pharmacol 1985; 15: 283–9.
Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ . Treatment of disseminated germ-cell tumors with cisplatin, bleomycin and either vinblastine or etoposide. N Engl J Med 1987; 316: 1435–40.
Pan QW, Liu BS, Liu J, Cai R, Wang YG, Qian C . Synergistic induction of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying TRAIL. Mol Cell Biochem 2007; 304: 315–23.
Pan QW, Zhong SY, Liu BS, Liu J, Cai R, Wang YG, et al. Enhanced sensitivity of hepatocellular carcinoma cells to chemotherapy with a Smac-armed oncolytic adenovirus. Acta Pharmacol Sin 2007; 28: 1996–2004.
Xiong J, Peng ZL, Tan X . Effects of adenoviral-mediated mda-7/IL-24 gene infection on the growth and drug-resistance of drug-resistant ovarian cancer cell lines. Sichuan Da Xue Xue Bao Yi Xue Ban 2007; 38: 433–6. Chinese.
Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L, et al. A controlled trial of ONYX-015, a replication-selective adenovirus, in combination with cisplatin and 5-FU in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–85.
Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (mda-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 2001; 20: 7051–63.
Liu XY, Gu JF . Targeting gene-virotherapy of cancer. Cell Res 2006; 16: 25–30.
Hajra KM, Tan L, Liu JR . Defective apoptosis underlies chemoresistance in ovarian cancer. Adv Exp Med Biol 2008; 622: 197–208.
Uyama N, Hatano E, Maetani Y, Isoda H, Shibata T, Taura K, et al. Efficacy and toxicity of transcatheter arterial chemoembolization with cisplatin suspended in lipiodol for unresectable hepatocellular carcinoma. Gan To Kagaku Ryoho 2008; 35: 775–80.
Kirn D . Clinical research results with dl1520 (Onyx-015), a replication-selective adenovirus for the treatment of cancer: what have we learned? Gene Ther 2001; 8: 89–98.
Kirn D . Oncolytic virotherapy for cancer with the adenovirus dl1520 (Onyx-015): results of phase I and II trials. Expert Opin Biol Ther 2001; 1: 525–38.
Fillastre JP, Raguenez-Viotte G . Cisplatin nephrotoxicity. Toxicol Lett 1989; 46: 163–75.
Arany I, Safirstein RL . Cisplatin nephrotoxicity. Semin Nephrol 2003; 23: 460–4.
Acknowledgements
We thank Prof Xin-yuan LIU for his thorough review and approval of this article and Kan CHEN for her help with cell culture. This work was supported by the Zhejiang Science and Technology Support Plan (No 2007C33027), National Natural Science Foundation of China (No 30800093, No 30801379), Science and Technology Commission of Shanghai Municipality (No 06DZ22032), National Basic Research Program of China (973 Program, No 2004 CB51804), Key Project of the Chinese Academy of Science (No KSCX2-YW-R-09, R-04), and Zhejiang Sci-Tech University Grant 0616033 to Prof Xin-yuan LIU.
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Wu, Ym., Zhang, Kj., Yue, Xt. et al. Enhancement of tumor cell death by combining cisplatin with an oncolytic adenovirus carrying MDA-7/IL-24. Acta Pharmacol Sin 30, 467–477 (2009). https://doi.org/10.1038/aps.2009.16
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DOI: https://doi.org/10.1038/aps.2009.16
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