Attenuated Salmonella Targets Prodrug Activating Enzyme Carboxypeptidase G2 to Mouse Melanoma and Human Breast and Colon Carcinomas for Effective Suicide Gene Therapy
Purpose: We engineered the oncolytic Salmonella typhimurium –derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs. Experimental Design: We charac...
Saved in:
Published in | Clinical cancer research Vol. 14; no. 13; pp. 4259 - 4266 |
---|---|
Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.07.2008
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Purpose: We engineered the oncolytic Salmonella typhimurium –derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2
(CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs.
Experimental Design: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug
activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured
by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with
postmortem analysis of bacterial and CPG2 concentration in the tumors.
Results: CPG2 is expressed within the bacterial periplasm. It activates prodrugs and induces cytotoxicity in human tumor cells but
not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 × 10 7 /g to 2 × 10 8 /g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to
6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of prodrugs further reduces significantly
the growth of the xenografts.
Conclusions: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce
the growth of tumors. However, in the presence of prodrugs activated by CPG2, this oncolytic effect is greatly increased.
We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment
of a range of cancers. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-07-4800 |