Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

Greco, Olga; Dachs, Gabi U.

doi:10.1002/1097-4652(2001)9999:9999<::aid-jcp1060>3.0.co;2-h

Cited by 238 publications

(150 citation statements)

References 129 publications

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“…[36][37][38] Others have also shown 5-FC conversion to 5-FU in patients receiving cytosine deaminase gene delivered via nonreplicating adenoviral vectors. 38,39 These preliminary results support future investigation of TAPET-CD at higher doses via intratumoral injection. However, since local regional therapeutics have limited utility in oncology a secondgeneration Salmonella vector expressing CD is undergoing preclinical development for potential intravenous injection.…”

Section: Discussionmentioning

confidence: 99%

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

et al. 2003

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We performed a pilot trial in refractory cancer patients to investigate the feasibility of intratumoral injection of TAPET-CD, an attenuated Salmonella bacterium expressing the E. coli cytosine deaminase gene. A total of three patients received three dose levels of TAPET-CD (3 Â 10 6 -3 Â 10 7 CFU/m 2 ) via intratumoral injection once every 28 days as long as progression of disease or intolerable toxicity was not observed. From days 4 to 14 of each 28 day cycle, patients also received 5-fluorocytosine (5-FC) at a dose of 100 mg/kg/day p.o. divided three times daily. Six cycles of treatment were administered. No significant adverse events clearly attributable to TAPET-CD were demonstrated. Two patients had intratumor evidence of bacterial colonization with TAPET-CD, which persisted for at least 15 days after initial injection. Conversion of 5-FC to 5-fluorouracil (5-FU) as a result of cytosine deaminase expression was demonstrated in these two patients. The tumor to plasma ratio of 5-FU for these two colonized patients was 3.0, demonstrating significantly increased levels of 5-FU at the site of TAPET-CD colonization and insignificant systemic spread of the bacteria. In contrast, the tumor to plasma ratio of 5-FU of the patient who did not show colonization of TAPET-CD was less than 1.0. These results support the principle that a Salmonella bacterium can be utilized as a delivery vehicle of the cytosine deaminase gene to malignant tissue and that the delivered gene is functional (i.e. able to convert 5-FC to 5-FU) at doses at or below 3 Â 10 7 CFU/m 2 .

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Section: Discussionmentioning

confidence: 99%

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

et al. 2003

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“…1,2 The rationale for this type of therapy is to increase the therapeutic index in cancer treatment. 3 Transfer of the herpes simplex virus type 1 thymidine kinase (HSV-TK) gene into tumor cells sensitizes them to the antiviral drug ganciclovir (GCV). [4][5][6][7] Numerous studies have demonstrated excellent cell killing with GCV in HSV-TK-expressing tumor cells both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

GCV phosphates are transferred between HeLa cells despite lack of bystander cytotoxicity

Gentry

Boucher

et al. 2005

Gene Ther

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The role of gap junctional intercellular communication (GJIC) in bystander killing with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) was evaluated in U251 cells expressing a dominant-negative connexin 43 cDNA (DN14), and in HeLa cells, reportedly devoid of connexin protein. These cell lines both exhibited 0% GJIC when assayed by Lucifer Yellow fluorescent dye microinjection. Bystander cytotoxicity was still apparent in 50:50 cocultures of DN14 and HSV-TK-expressing U251 cells, but not in 50:50 cocultures of HeLa cells. However, the sensitivity of HeLa HSV-TK-expressing cells to GCV decreased nearly 100-fold (IC 90 ¼ 109 mM) when cocultured with bystander cells compared to results in 100% cultures of HSV-TK-expressing cells (IC 90 ¼ 1.2 mM). A more sensitive flow cytometry technique to measure GJIC over 24 h revealed that the DN14 and HeLa cells exhibited detectable levels of communication (29 and 23%, respectively). Transfer of phosphorylated GCV to HeLa bystander cells occurred within 4 h after drug addition, and GCV triphosphate (GCVTP) accumulated to 213784 pmol/10 6 cells after 24 h. In addition, GCVTP levels were decreased in HSV-TK-expressing cells in coculture (867733 pmol/10 6 cells) compared to 100% cultures of HSV-TK-expressing cells (17737188 pmol/10 6 cells). The half-life of GCVTP in the HSV-TK-expressing cells was approximately four times that measured in the bystander cells (12.3 and 3.1 h, respectively). These data suggest that the lack of bystander cytotoxicity in HeLa cocultures is due to low transfer of phosphorylated GCV and a rapid half-life of GCVTP in the bystander cells. Thus, GCV phosphate transfer to non-HSV-TK-expressing bystander cells may mediate either bystander cell killing or sparing of HSV-TK-positive cells, depending upon the cell specific drug metabolism.

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“…Other gene therapies for human colorectal cancer, such as enzyme/prodrug systems (HSVtk/ganciclovir; CD/5-fluorocytosine) and immune-gene therapy based on cytokine or tumor antigen expression to induce tumor immunity (eg CEA), have not yet improved prognosis. 4,[5][6][7] Elucidation of the basic molecular mechanisms of colorectal cancer and determination of a novel target for gene therapy are thus required.…”

Section: Introductionmentioning

confidence: 99%

Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer

et al. 2004

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Gene directed enzyme/prodrug therapy of cancer: Historical appraisal and future prospectives

Cited by 238 publications

References 129 publications

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

GCV phosphates are transferred between HeLa cells despite lack of bystander cytotoxicity

Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer

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