Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector

Takahashi, Manabu; Valdés, Gilmer; Hiraoka, Kenzo; Inagaki, Akihito; Kamijima, Shuichi; Micewicz, Ewa D.; Gruber, Harry E.; Robbins, Joan M.; Jolly, Douglas J.; McBride, William H.; Iwamoto, Keisuke S.; Kasahara, Noriyuki

doi:10.1038/cgt.2014.38

Cited by 33 publications

(33 citation statements)

References 24 publications

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“…As is indicated in figure 4, the growth inhibitory effects of combined PDT and CD-GDEPT were also pronounced for the PDT before 5-FC sequence, indicating that PDT sensitized the tumor cell to the toxic metabolites converted from the prodrug. Similar effects were observed following brief exposure of CD positive tumor cells to 5-FC followed by ionizing radiation (equivalent to a “radiation after” sequence) [31]. These authors could demonstrate an enhanced effect of radiation both in vitro and in vivo, which they attributed to a sensitization to radiation by CD-GDEPT.…”

Section: Discussionmentioning

confidence: 53%

Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy

Christie

Pomeroy

Nair

et al. 2017

Photodiagnosis and Photodynamic Therapy

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Introduction Gene-directed enzyme prodrug therapy (GDEPT) employing the cytosine deaminase (CD) gene, which encodes an enzyme that converts the nontoxic agent 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU), has shown promise both in experimental animals and in clinical trials. Nevertheless, with the transfection systems available presently the percentage of tumor cells incorporating the desired gene is usually too low for successful therapy. We have examined the ability of photodynamic therapy (PDT) to enhance the efficacy of the metabolites, converted from 5-FC by CD gene transfected rat glioma cells. Methods Hybrid tumor cell spheroids consisting of CD positive and CD negative F98 glioma cells in varying ratios were used as in vitro tumor models. PDT was performed with the photosensitizer AlPcS2a and λ = 670nm laser irradiance, both before and after confrontation with 5-FC. Results PDT increased the toxicity of 5-FU either as pure drug or derived from monolayers of CD positive cells chalanged with 5-FC. PDT in combination with 5-FC resulted in a significantly enhanced inhibition of hybrid spheroid growth compared to non light treated controls. This was the case even at tumor to producer cell ratios as high as 40:1. Conclusion The results of the present study show that GDEPT and PDT interact in a synergistic manner over a range of prodrug concentration and tumor to transfected cell ratios. The degree of synergy was significant regardless if PDT treatment was given before or after 5-FC administration. The highest degree of interaction was observed though, when PDT was delivered prior to prodrug exposure.

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Section: Discussionmentioning

confidence: 53%

Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy

Christie

Pomeroy

Nair

et al. 2017

Photodiagnosis and Photodynamic Therapy

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“…The newly diagnosed setting also provides an opportunity to leverage Toca 511 + Toca FC activity with radiation therapy and temozolomide as reported in preclinical models. 47,48 The ability of Toca 511 + Toca FC therapy to alter immunesuppressive networks within the tumor microenvironment and cause cancer cell death may provide a mechanism for turning tumors with low immunogenic potential and immune activity into tumors actively destroyed by the immune system. Toca 511 + Toca FC likely breaks immune tolerance to the notoriously recalcitrant HGG by increasing both immunogenicity and immune activity within the tumor microenvironment.…”

Section: Neuro-oncologymentioning

confidence: 99%

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

et al. 2018

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Section: Introductionmentioning

confidence: 99%

“…CD-based cancer gene therapy has proven to be effective in chemotherapyresistant cancer cell lines, 31,32 in combination with chemotherapy, 4 and to enhance the effect of radiotherapy. 33 To further improve the wild-type CD, we developed a codon-optimized, 7 heat-stabilized 34 yeast CD (yCD) gene, which resulted in an approximate 3-fold greater enzyme-specific activity compared with the wild-type protein when incorporated into Toca 511. The primary cytotoxic effects of 5-FU occur through two distinct pathways: inhibition of DNA synthesis by the conversion of 5-FU to fluorodeoxyuridine monophosphate (FdUMP) 2,11,35 and perturbation of RNA synthesis by the conversion of 5-FU to 5-fluorouridine triphosphate (5-FUTP) 3,16,31,36 through 5-fluorouridine monophosphate (5-FUMP) and 5-fluorouridine diphosphate (5-FUDP) intermediates.…”

mentioning

confidence: 99%

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

Twitty

DiagoOscar

HoganDaniel

et al. 2016

Human Gene Therapy Methods

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Toca 511 is a modified retroviral replicating vector based on Moloney c-retrovirus with an amphotropic envelope. As an investigational cancer treatment, Toca 511 preferentially infects cancer cells without direct cell lysis and encodes an enhanced yeast cytosine deaminase that converts the antifungal drug 5-fluorocytosine to the anticancer drug, 5-fluorouracil. A panel of established human cancer cell lines, derived from glioblastoma, colon, and breast cancer tissue, was used to evaluate parameters critical for effective anticancer activity. Gene transfer, cytosine deaminase production, conversion of 5-fluorocytosine to 5-fluorouracil, and subsequent cell killing occurred in all lines tested. We observed >50% infection within 25 days in all lines and 5-fluorocytosine LD 50 values between 0.02 and 6 lg/ml. Although we did not identify a small number of key criteria, these studies do provide a straightforward approach to rapidly gauge the probability of a Toca 511 and 5-fluorocytosine treatment effect in various cancer indications: a single MTS assay of maximally infected cancer cell lines to determine 5-fluorocytosine LD 50 . The data suggest that, although there can be variation in susceptibility to Toca 511 and 5-fluorocytosine because of multiple mechanistic factors, this therapy may be applicable to a broad range of cancer types and individuals.INTRODUCTION THE IDEA OF USING replication-competent viruses as a direct therapy for the treatment of cancer emerged more than a century ago.1 The c-retrovirus murine leukemia virus (MLV) is an attractive tool for tumor gene therapy, as its nonlytic life cycle and requirement for host cell division allow for tumor-selective enhanced gene transfer 2 and spread throughout the tumor. This MLV-based approach to gene therapy has been used to deliver and express the cytosine deaminase (CD) gene into tumor cells, providing a specific conversion of the well-tolerated antifungal prodrug, 5-fluorocytosine (5-FC), into the potent chemotherapeutic 5-fluorouracil (5-FU), which has been well established in preclinical studies. [2][3][4][5][6] Building on this concept, Tocagen's retroviral replicating vector (RRV) named Toca 511 7 (vocimagene amiretrorepvec) preferentially infects tumors without immediate cell killing and encodes an optimized yeast cytosine deaminase (yCD) that converts 5-FC into 5-FU within infected tumors. 3,4,7,8 We are currently investigating the clinical utility, in recurrent high-grade glioma, of Toca 511 in combination with Toca FC, an investigational orally administered extended-release formulation of 5-FC (NCT01470794, NCT01156584, NCT01985256, and NCT02414165).CD is lacking or poorly expressed in most human cells but is often expressed in yeast and bacteria as part of the pyrimidine salvage pathway and is responsible for converting cytosine to uracil and ammonia. CD also catalyzes, by means of a deamination step, the conversion of the prodrug 5-FC to the chemotherapeutic drug 5-FU 9,10 within cancer cells expressing gene therapy-delivered CD. CDbased prodru...

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Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector

Cited by 33 publications

References 24 publications

Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy

Photodynamic therapy enhances the efficacy of gene-directed enzyme prodrug therapy

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

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