Anti-neoplastic glucuronide prodrug treatment of human tumor cells targeted with a monoclonal antibody-enzyme conjugate

Roffler, Steven R.; Wang, Shing-Ming; Chern, Ji‐Wang; Yeh, Ming‐Yang; Tung, E.

doi:10.1016/0006-2952(91)90612-9

Cited by 68 publications

(30 citation statements)

References 14 publications

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“…Toxicity of 9AC and pHAM to DH5a-lux/bG strains DH5a-lux/bG strains were cultured up to OD 600 ¼ 0.35, then the DH5a-lux/bG were subdivided into triplicate and incubated with graded amounts of 9AC, a topoisomerase I inhibitor, or p-hydroxyaniline mustard (pHAM), 25 an alkylating agent, at 37 1C for 3 and 6 h. The growth inhibition of DH5a-lux/bG was measured by the spectrophotometer at OD 600 nm .…”

Section: Bacteria Cells and Animalsmentioning

confidence: 99%

Tumor-targeting prodrug-activating bacteria for cancer therapy

Cheng

Chuang

et al. 2008

Cancer Gene Ther

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Increasing the specificity of chemotherapy may improve the efficacy of cancer treatment. Toward this aim, we developed a strain of bacteria to express enzymes for selective prodrug activation and non-invasive imaging in tumors. b-glucuronidase and the luxCDABE gene cluster were expressed in the DH5a strain of Escherichia coli to generate DH5a-lux/bG. These bacteria emitted light for imaging and hydrolyzed the glucuronide prodrug 9ACG to the topoisomerase I inhibitor 9-aminocamptothecin (9AC). By optical imaging, colony-forming units (CFUs) and staining for bG activity, we found that DH5a-lux/bG preferentially localized and replicated within CL1-5 human lung tumors in mice. The intensity of luminescence, CFU and bG activity increased with time, indicating bacterial replication occurred in tumors. In comparison with DH5a-lux/bG, 9AC or 9ACG treatment, combined systemic administration of DH5a-lux/bG followed by 9ACG prodrug treatment significantly (Po0.005) delayed the growth of CL1-5 tumors. Our results demonstrate that prodrug-activating bacteria may be useful for selective cancer chemotherapy.

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Section: Bacteria Cells and Animalsmentioning

confidence: 99%

Tumor-targeting prodrug-activating bacteria for cancer therapy

Cheng

Chuang

et al. 2008

Cancer Gene Ther

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“…15 Recombinant Escherichia coli-derived bG was produced as described. 16 Succinimidyl succinate poly(ethylene glycol) (PEG) (5 kDa) was purchased from Sigma Chemical Company, St Louis, MO.…”

Section: Reagentsmentioning

confidence: 99%

Hapten-directed targeting to single-chain antibody receptors

et al. 2004

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Artificial recombinant receptors may be useful for selectively targeting imaging and therapeutic agents to sites of gene expression. To evaluate this approach, we developed transgenes to express highly on cells a single-chain antibody (scFv) against the hapten 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one (phOx). A phOx enzyme conjugate was created by covalently attaching phOx molecules to polyethylene glycol (PEG)-modified b-glucuronidase. Cells expressing phOx scFv but not control scFv receptors were selectively killed after exposure to -glucuronidase derivatized with phOx and PEG (phOx-bG-PEG) and a glucuronide prodrug (phydroxy aniline mustard b-D-glucuronide, HAMG) of p-hydroxyaniline mustard. Targeted activation of HAMG produced bystander killing of receptor-negative cells in mixed populations containing as few as 10% phOx-receptor-positive cells. Functional phOx scFv receptors were stably expressed on B16-F1 melanoma tumors in vivo. Treatment of mice bearing established phOx-receptorpositive tumors with phOx-bG-PEG and HAMG significantly (Pp.0005) suppressed tumor growth as compared with treatment with bG-PEG and HAMG or prodrug alone. phOx was unstable in the serum, suggesting alternative haptens may be more suitable for in vivo applications. Our results show that therapeutic agents can be targeted to artificial hapten receptors in vitro and in vivo. The expression of artificial receptors on target cells may allow preferential delivery of therapeutic or imaging molecules to sites of transgene expression.

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“…8 Polyinosinic-polycytidylic acid and egg ovalbumin were from Sigma (St. Louis, MO). Recombinant ␤G was produced as described.…”

Section: Reagentsmentioning

confidence: 99%

Potentiation of antitumor immunity by antibody-directed enzyme prodrug therapy

et al. 2001

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Antibody-directed enzyme prodrug therapy (ADEPT) has displayed antitumor activity in animal models and clinical trials. We examined whether antitumor immunity is generated during ADEPT by employing an immunoenzyme composed of the monoclonal antibody (MAb) RH1 conjugated to ␤-glucuronidase to target rat AS-30D hepatocellular carcinoma tumors. A glucuronide prodrug of p-hydroxyaniline mustard was used to treat malignant ascites after immunoenzyme localization at the cancer cells. ADEPT cured more than 96% of Sprague-Dawley rats bearing advanced malignant ascites, and all cured rats were protected from a lethal challenge of AS-30D cells. Immunization with radiation-killed AS-30D cells or AS-30D cells coated with immunoenzyme did not provide tumor protection. Likewise, ex vivo treatment of tumor cells by ADEPT before injection into rats did not protect against a tumor challenge. AS-30D and N1-S1 hepatocellular carcinoma cells but not unrelated syngeneic tumor cells were lysed by peritoneal exudate cells isolated from ADEPT-cured rats. Depletion of CD8 ؉ but not CD4 ؉ T cells or natural killer (NK) cells reduced the cytolytic activity of peritoneal lymphocytes. ADEPT did not cure tumor-bearing rats depleted of CD4 ؉ and CD8 ؉ T cells even though it was curative when given 7 days after tumor transplantation in rats with an intact immune system, indicating that ADEPT can synergize with host immunity to increase therapeutic efficacy. These results have important implications for the clinical application of ADEPT.

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Anti-neoplastic glucuronide prodrug treatment of human tumor cells targeted with a monoclonal antibody-enzyme conjugate

Cited by 68 publications

References 14 publications

Tumor-targeting prodrug-activating bacteria for cancer therapy

Tumor-targeting prodrug-activating bacteria for cancer therapy

Hapten-directed targeting to single-chain antibody receptors

Potentiation of antitumor immunity by antibody-directed enzyme prodrug therapy

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