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Bystander killing of tumour cells by antibody-targeted enzymatic activation of a glucuronide prodrug.

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  • 1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
      Authors
    • Cheng TL 1
    (1 author)

British Journal of Cancer, 01 Mar 1999, 79(9-10):1378-1385
https://doi.org/10.1038/sj.bjc.6690221 PMID: 10188879 PMCID: PMC2362709

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Abstract 

RHI-betaG-PEG, formed by linking poly(ethylene glycol)-modified beta-glucuronidase to Mab RH1, was employed to examine bystander killing of antigen-negative N1S1 rat hepatoma cells by activation of a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at antigen-positive AS-30D rat hepatoma cells. Sequential treatment of cells with 10 microg ml(-1) RH1-betaG-PEG and 20 microM BHAMG was not toxic to N1S1 cells but killed 99% of AS-30D cells. Over 98% of N1S1 cells, however, were killed in mixed populations containing as few as 2% AS-30D cells after identical treatment, demonstrating an in vitro bystander effect. Subcutaneous injection of AS-30D and N1S1 cells in BALB/c nu/nu mice produced solid tumours containing both cells. Uptake of radiolabelled RH1-betaG-PEG in solid AS-30D and mixed AS-30D/N1S1 tumours was 11.6 and 9.3 times greater than a control antibody conjugate 120 h after i.v. injection. Intravenous treatment with RH1-betaG-PEG and BHAMG cured seven of seven nude mice bearing solid s.c. AS-30D tumours and significantly delayed, compared with control conjugate and prodrug treatment, the growth of mixed N1S1/AS-30D tumours with one cure, showing that targeted activation of BHAMG kills bystander tumour cells in vivo.

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Logo of brjcancerBJC HomepageBJC Advance online publicationBJC Current IssueSubmitting an article to BJCWeb feeds
Br J Cancer. 1999 Mar; 79(9-10): 1378–1385.
PMCID: PMC2362709
PMID: 10188879

Bystander killing of tumour cells by antibody-targeted enzymatic activation of a glucuronide prodrug

T L Cheng,1,2 S L Wei,3 B M Chen,1 J W Chern,4 M F Wu,5 P W Liu,3 and S R Roffler1
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Abstract

RHI-βG-PEG, formed by linking poly(ethylene glycol)-modified β-glucuronidase to Mab RH1, was employed to examine bystander killing of antigen-negative N1S1 rat hepatoma cells by activation of a glucuronide prodrug (BHAMG) of p-hydroxyaniline mustard (pHAM) at antigen-positive AS-30D rat hepatoma cells. Sequential treatment of cells with 10 μg ml−1 RH1-βG-PEG and 20 μM BHAMG was not toxic to N1S1 cells but killed 99% of AS-30D cells. Over 98% of N1S1 cells, however, were killed in mixed populations containing as few as 2% AS-30D cells after identical treatment, demonstrating an in vitro bystander effect. Subcutaneous injection of AS-30D and N1S1 cells in BALB/c nu/nu mice produced solid tumours containing both cells. Uptake of radiolabelled RH1-βG-PEG in solid AS-30D and mixed AS-30D/N1S1 tumours was 11.6 and 9.3 times greater than a control antibody conjugate 120 h after i.v. injection. Intravenous treatment with RH1-βG-PEG and BHAMG cured seven of seven nude mice bearing solid s.c. AS-30D tumours and significantly delayed, compared with control conjugate and prodrug treatment, the growth of mixed N1S1/AS-30D tumours with one cure, showing that targeted activation of BHAMG kills bystander tumour cells in vivo. © 1999 Cancer Research Campaign

Keywords: bystander effect, antibody-directed enzyme prodrug therapy, monoclonal antibody, prodrugs, β-glucuronidase, immunoconjugates

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Selected References

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