In situ delivery of suicide genes for cancer treatment

Blaese, R. Michael; Ishii-Morita, H; Mullen, CA; Ramsey, Jay; Ram, Zvi; Oldfield, Edward H.; Culver, Kenneth W.

doi:10.1016/0959-8049(94)90482-0

Cited by 35 publications

(13 citation statements)

References 7 publications

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“…4 One approach for cancer treatment using gene transfer Another approach for cancer treatment is the use of involves immune activation or enhancement employing suicide genes. 5 The best-studied suicide gene to date is genes for various cytokines or costimulatory molecules.…”

Section: Introductionmentioning

confidence: 99%

“…A surprisresults is the so-called 'bystander' effect that confers cytoingly large number of cytokines are able to induce a local toxicity to the neighboring nontransduced cells. 5 The response causing tumor rejection. 1 In addition, similar original studies were based on the use of retrovirus (Rv)-successful tumor rejections have been reported after mediated gene transfer.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1

1997

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In a cancer gene therapy model recombinant adenoviruses challenge with wild-type tumor but not from challenges with expressing the herpes simplex virus thymidine kinase an unrelated syngeneic tumor cell line. Since cytotoxic T (HSVtk) gene were injected into tumors in situ, either alone lymphocyte responses in this tumor model were weak, we or in combination with adenoviruses (Avs) engineered to analyzed cytokine secretion from spleen cells of treated express IL-2, IL-6 or the costimulatory molecule B7-1.animals. The best correlate of antitumor immunity in this HSVtk phosphorylates the prodrug ganciclovir, thus conmodel was enhanced secretion of GM-CSF, while verting it into an antimetabolite which kills not only HSVtk secretion of IL-2, IL-6 and IFN␥ was also frequently expressing cells, but also by the 'bystander effect', neighincreased but not as consistently. The enhanced IFN␥ boring untransduced tumor cells. The tumors regressed in secretion associated with unchanged IL-4 secretion sug-80% of mice upon AvTK/ganciclovir treatment; combigests that AvTK treatment results in a predominantly Th1-nations with AvIL-2, AvIL-6, or AvB7-1 did not improve mediated antitumor immune response. these results. Cured mice were protected from further

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1

1997

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“…The efficacy of each of the two SG/PD approaches has been shown in a number of in vitro experiments and in in vivo models (reviewed in Ref. 7). The synergistic interaction of the pharmacologically active metabolites of these SG/PD systems has been well established 8 and has been applied in combination chemotherapy for many years.…”

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confidence: 99%

Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine

et al. 2000

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The success of chemotherapeutic intervention is limited because the necessary high local drug doses cannot be achieved without systemic toxicity. Application of suicide genes (SGs) and direct conversion of prodrugs (PDs) to toxic metabolites in situ by SGs may enhance the efficacy of chemotherapy. To evaluate this strategy in two murine breast cancer models, TS/A and GR, we injected cellulose sulfate capsules harboring cat kidney cells expressing the SGs cytosine deaminase and cytochrome P450 2B1 (CYP2B1) intratumorally. The PDs 5-fluorocytosine and ifosfamide were administered in 3-day intervals. The effect of in situ chemotherapy with each PD alone and the combination was analyzed over a period of 100 days. The results reveal that for TS/A tumors, the antitumoral effect mediated by CYP2B1 is more efficient than that of cytosine deaminase, whereas for GR tumors, both systems worked equally well. Furthermore, we find additive toxicity using both SG/PD systems for both TS/A and GR tumors. Cancer Gene Therapy (2000) 7, 629 -636

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“…4 Thus, the measurement of the bystander effect in vitro may underestimate the potential of suicidebased cancer gene therapy. However, although suicide gene therapy can have a therapeutic benefit in vitro, 23 ± 25 in animal models 26 and in clinical trials, 23 it has yet to be used to cure a patient with cancer. To achieve cures it will probably be necessary to additionally activate the patient's immune system to detect any residual tumor cells at the site of the primary tumor and to eliminate distant metastases.…”

Section: Discussionmentioning

confidence: 99%

Necrotic, rather than apoptotic, cell death caused by cytochrome P450–activated ifosfamide

et al. 2001

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Feline kidney cells were transfected with a vector overexpressing cytochrome P450 2B1 ( CYP2B1 ) . Transfected cells acquired a new specific biochemical activity, which could be demonstrated by a rapid CYP2B1 detection assay and showed selective sensitivity to the antitumorigenic prodrug ifosfamide ( IFO ) . Further, the cell -killing effect was also mediated on nonmodified cells like feline kidney cells, mouse lymphoma, and human pancreatic cells in the vicinity of the CYP2B1 -expressing cells due to the diffusible nature of the activated IFO metabolites. One of these, phosphoramide mustard, causes interstrand DNA cross -linking and it has been thought that the inability to repair this damage results in apoptosis. Surprisingly, our results clearly demonstrate a necrotic mechanism of IFO -induced cell death. This may have important implications for the activation of the immune system during CYP2B1 / IFO suicide gene therapy of cancer. Cancer Gene Therapy ( 2001 ) 8, 220 ± 230

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In situ delivery of suicide genes for cancer treatment

Cited by 35 publications

References 7 publications

Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1

Characterization of the antitumor immune response generated by treatment of murine tumors with recombinant adenoviruses expressing HSVtk, IL-2, IL-6 or B7-1

Combined chemotherapy of murine mammary tumors by local activation of the prodrugs ifosfamide and 5-fluorocytosine

Necrotic, rather than apoptotic, cell death caused by cytochrome P450–activated ifosfamide

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