Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in combination with vincristine (VCR) on retinoblastoma in vitro, the cell viability, cell cycle effects and apoptotic activity of HXO-RB 44 cells treated with SG600, VCR or SG600 plus VCR were measured using a cell counting kit-8-based procedure and flow cytometry. Western blot analysis for Akt, p-Akt, p-p53 and p-Rb protein was performed to investigate the underlying mechanisms of combined therapy. The combination therapy exerted a synergistic antitumor effect via a type of G 2/M and S phase arrest rather than the induction of apoptosis. The combination of VCR and SG600 further reduced Akt phosphorylation compared with cells treated with VCR alone, suggesting that SG600 could overcome chemoresistance, perhaps by down-regulating Akt in RB cells. An increase in the expression of p-p53 and decrease in p-Rb expression in HXO-RB 44 after co-treatment might be associated with cell cycle block. Western blot examination revealed that VCR might enhance SG600 replication. These results suggest that viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma.
References
[1]
Devesa, S.S. The incidence of retinoblastoma. Am. J. Ophthalmol 1975, 80, 263–265.
[2]
Murphree, A.L.; Villablanca, J.G.; Deegan, W.F., III; Sato, J.K.; Malogolowkin, M.; Fisher, A.; Parker, R.; Reed, E.; Gomer, C.J. Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch. Ophthalmol. 1996, 114, 1348–1356.
[3]
Abramson, D.H.; Frank, C.M.; Dunkel, I.J. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 1999, 106, 1947–1950.
[4]
Chan, H.S.; Canton, M.D.; Gallie, B.L. Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res 1989, 9, 469–474.
[5]
Chan, H.S.; Thorner, P.S.; Haddad, G.; Gallie, B.L. Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression. Ophthalmology 1991, 98, 1425–1431.
[6]
Wilson, M.W.; Fraga, C.H.; Rodriguez-Galindo, C.; Hagedorn, N.; Leggas, M.L.; Stewart, C. Expression of the multi-drug resistance proteins and the pregnane X receptor in treated and untreated retinoblastoma. Curr. Eye Res 2009, 34, 386–394.
[7]
Wilson, M.W.; Fraga, C.H.; Fuller, C.E.; Rodriguez-Galindo, C.; Mancini, J.; Hagedorn, N.; Leggas, M.L.; Stewart, C.F. Immunohistochemical detection of multidrug-resistant protein expression in retinoblastoma treated by primary enucleation. Investig. Ophthalmol. Vis. Sci 2006, 47, 1269–1273.
[8]
Cun, B.; Song, X.; Jia, R.; Zhao, X.; Wang, H.; Ge, S.; Fan, X. Combination of oncolytic adenovirus and dacarbazine enhances antitumor ability against uveal melanoma cells via cell cycle block. Cancer Biol. Ther 2012, 13, 77–84.
[9]
Song, X.; Zhou, Y.; Jia, R.; Xu, X.; Wang, H.; Hu, J.; Ge, S.; Fan, X. Inhibition of retinoblastoma in vitro and in vivo with conditionally replicating oncolytic adenovirus H101. Investig. Ophthalmol. Vis. Sci 2010, 51, 2626–2635.
[10]
Zhang, H.; Wang, H.; Zhang, J.; Qian, G.; Niu, B.; Fan, X.; Lu, J.; Hoffman, A.R.; Hu, J.F.; Ge, S. Enhanced therapeutic efficacy by simultaneously targeting two genetic defects in tumors. Mol. Ther. J. Am. Soc. Gene Ther 2009, 17, 57–64.
[11]
Gomez-Manzano, C.; Alonso, M.M.; Yung, W.K.; McCormick, F.; Curiel, D.T.; Lang, F.F.; Jiang, H.; Bekele, B.N.; Zhou, X.; Alemany, R.; et al. Delta-24 increases the expression and activity of topoisomerase I and enhances the antiglioma effect of irinotecan. Clin. Cancer Res 2006, 12, 556–562.
Wang, X.; Su, C.; Cao, H.; Li, K.; Chen, J.; Jiang, L.; Zhang, Q.; Wu, X.; Jia, X.; Liu, Y.; et al. A novel triple-regulated oncolytic adenovirus carrying p53 gene exerts potent antitumor efficacy on common human solid cancers. Mol. Cancer Ther 2008, 7, 1598–1603.
[14]
Friend, S.H.; Bernards, R.; Rogelj, S.; Weinberg, R.A.; Rapaport, J.M.; Albert, D.M.; Dryja, T.P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986, 323, 643–646.
[15]
Laurie, N.A.; Donovan, S.L.; Shih, C.S.; Zhang, J.; Mills, N.; Fuller, C.; Teunisse, A.; Lam, S.; Ramos, Y.; Mohan, A.; et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006, 444, 61–66.
[16]
Laurie, N.A.; Shih, C.S.; Dyer, M.A. Targeting MDM2 and MDMX in retinoblastoma. Curr. Cancer Drug Targets 2007, 7, 689–695.
[17]
Marine, J.C.; Dyer, M.A.; Jochemsen, A.G. MDMX: From bench to bedside. J. Cell Sci 2007, 120, 371–378.
[18]
Ottolino-Perry, K.; Diallo, J.S.; Lichty, B.D.; Bell, J.C.; McCart, J.A. Intelligent design: Combination therapy with oncolytic viruses. Mol. Ther. J. Am. Soc. Gene Ther 2010, 18, 251–263.
[19]
Cheema, T.A.; Kanai, R.; Kim, G.W.; Wakimoto, H.; Passer, B.; Rabkin, S.D.; Martuza, R.L. Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts. Clin. Cancer Res 2011, 17, 7383–7393.
[20]
Hoffmann, D.; Bayer, W.; Wildner, O. Local and distant immune-mediated control of colon cancer growth with fusogenic membrane glycoproteins in combination with viral oncolysis. Hum. Gene Ther 2007, 18, 435–450.
[21]
Cinatl, J., Jr; Cinatl, J.; Michaelis, M.; Kabickova, H.; Kotchetkov, R.; Vogel, J.U.; Doerr, H.W.; Klingebiel, T.; Driever, P.H. Potent oncolytic activity of multimutated herpes simplex virus G207 in combination with vincristine against human rhabdomyosarcoma. Cancer Res. 2003, 63, 1508–1514.
[22]
De Potter, P. Current treatment of retinoblastoma. Curr. Opin. Ophthalmol 2002, 13, 331–336.
[23]
Balwierz, W.; Pietrys, D.; Romanowska-Dixon, B.; Kobylarz, J.; Pawinska-Wasikowska, K.; Moryl-Bujakowska, A. Results of combined chemotherapy and local ophtalmic therapy for intraocular retinoblastoma. Przegl. Lek 2010, 67, 404–408.
[24]
Qian, J.; Xue, K.; Gao, Y.J.; Yuan, Y.F.; Shan, H.D.; Bi, Y.W. Clinical therapeutic efficiency of chemoreduction and local therapy for children with retinoblastoma (in chinese). Zhonghua Yanke Zazhi 2010, 46, 312–316.
[25]
Kim, H.; Lee, J.W.; Kang, H.J.; Park, H.J.; Kim, Y.Y.; Shin, H.Y.; Yu, Y.S.; Kim, I.H.; Ahn, H.S. Clinical results of chemotherapy based treatment in retinoblastoma patients: A single center experience. Cancer Res. Treat 2008, 40, 164–171.
[26]
Shields, C.L.; Shields, J.A. Basic understanding of current classification and management of retinoblastoma. Curr. Opin. Ophthalmol 2006, 17, 228–234.
[27]
Turaka, K.; Shields, C.L.; Meadows, A.T.; Leahey, A. Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr. Blood Cancer 2011, 59, 121–125.
[28]
Ji, X.; Zhang, J.; Cheng, L.; Wei, F.; Li, H.; Liu, X.; Chen, X.; Li, C.; Wang, Y.; Huang, Q. Oncolytic adenovirus delivering herpes simplex virus thymidine kinase suicide gene reduces the growth of human retinoblastoma in an in vivo mouse model. Exp. Eye Res 2009, 89, 193–199.
[29]
Gallie, B.L.; Dunn, J.M.; Chan, H.S.; Hamel, P.A.; Phillips, R.A. The genetics of retinoblastoma. Relevance to the patient. Pediatr. Clin. North Am 1991, 38, 299–315.
[30]
Abramson, D.H.; Schefler, A.C. Update on retinoblastoma. Retina 2004, 24, 828–848.
[31]
Nevins, J.R. E2F: A link between the Rb tumor suppressor protein and viral oncoproteins. Science 1992, 258, 424–429.
[32]
Hennessy, B.T.; Smith, D.L.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/Akt pathway for cancer drug discovery. Nat. Rev. Drug Discov 2005, 4, 988–1004.
[33]
Gu, P.; Su, Y.; Guo, S.; Teng, L.; Xu, Y.; Qi, J.; Gong, H.; Cai, Y. Over-expression of COX-2 induces human ovarian cancer cells (CAOV-3) viability, migration and proliferation in association with PI3-k/Akt activation. Cancer Investig 2008, 26, 822–829.
[34]
Zhang, H.; Li, B.; Bai, S.W.; Wang, H.J. Constitutively active Akt contributes to vincristine resistance in human retinoblastoma cells. Cancer Investig 2010, 28, 156–165.
[35]
Bernt, K.M.; Steinwaerder, D.S.; Ni, S.; Li, Z.Y.; Roffler, S.R.; Lieber, A. Enzyme-activated prodrug therapy enhances tumor-specific replication of adenovirus vectors. Cancer Res 2002, 62, 6089–6098.