Glioblastoma survival in the United States before and during the temozolomide era. Thresholds of O6-alkylguanine-DNA alkyltransferase which confer significant resistance of human glial tumor xenografts to treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea or temozolomide. Kokkinakis DM, Bocangel DB, Schold SC, Moschel RC, Pegg AE. MGMT gene silencing and benefit from temozolomide in glioblastoma. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Ostermann S et al. Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Expert Opin Drug Saf 2009 8: 493–499.Ĭohen MH, Johnson JR, Pazdur R. The safety of temozolomide in the treatment of malignancies. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Ostertag D, Amundson KK, Lopez Espinoza F, Martin B, Buckley T, Galvao da Silva AP et al. Design and selection of toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression. Perez OD, Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A et al. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ.

However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma.

Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase ( CD) gene to tumors in orthotopic glioma models.

Toca nature online