Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector.

Abstract

Patients with the most common and aggressive form of high-grade glioma, glioblastoma multiforme, have poor prognosis and few treatment options. In 2 immunocompetent mouse brain tumor models (CT26-BALB/c and Tu-2449-B6C3F1), we showed that a nonlytic retroviral replicating vector (Toca 511) stably delivers an optimized cytosine deaminase prodrug activating gene to the tumor lesion and leads to long-term survival after treatment with 5-fluorocytosine (5-FC). Survival benefit is dose dependent for both vector and 5-FC, and as few as 4 cycles of 5-FC dosing after Toca 511 therapy provides significant survival advantage. In the virally permissive CT26-BALB/c model, spread of Toca 511 to other tissues, particularly lymphoid tissues, is detectable by polymerase chain reaction (PCR) over a wide range of levels. In the Tu-2449-B6C3F1 model, Toca 511 PCR signal in nontumor tissues is much lower, spread is not always observed, and when observed, is mainly detected in lymphoid tissues at low levels. The difference in vector genome spread correlates with a more effective antiviral restriction element, APOBEC3, present in the B6C3F1 mice. Despite these differences, neither strain showed signs of treatment-related toxicity. These data support the concept that, in immunocompetent animals, a replicating retroviral vector carrying a prodrug activating gene (Toca 511) can spread through a tumor mass, leading to selective elimination of the tumor after prodrug administration, without local or systemic pathology. This concept is under investigation in an ongoing phase I/II clinical trial of Toca 511 in combination with 5-FC in patients with recurrent high-grade glioma (www.clinicaltrials.gov NCT01156584).

• Authors: Derek Ostertag, Karin K Amundson, Fernando Lopez Espinoza, Bryan Martin, Taylor Buckley, Ana Paula Galvão da Silva, Amy H Lin, David T Valenta, Omar D Perez, Carlos E Ibañez, Ching-I Chen, Pär L Pettersson, Ryan Burnett, Veronika Daublebsky, Juraj Hlavaty, Walter Gunzburg, Noriyuki Kasahara, Harry E Gruber, Douglas J Jolly, Joan M Robbins
• Journal: Neuro-oncology (Neuro Oncol) Vol. 14 Issue 2 Pg. 145-59 (Feb 2012) ISSN: 1523-5866 [Electronic] England
• PMID: 22070930 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Flucytosine
• Fluorouracil

Topics

• Animals
• Brain Neoplasms (drug therapy, mortality, therapy)
• Combined Modality Therapy
• Disease Models, Animal
• Female
• Flucytosine (metabolism, pharmacology, therapeutic use)
• Fluorouracil (metabolism, pharmacology)
• Genetic Therapy
• Genetic Vectors (administration & dosage)
• Glioma (drug therapy, genetics, mortality, therapy)
• Leukemia Virus, Murine (genetics)
• Mice
• Mice, Inbred BALB C
• Survival Analysis
• Tumor Cells, Cultured