| Frequent, moderate-dose cyclophosphamide administration improves the efficacy of cytochrome P-450/cytochrome P-450 reductase-based cancer gene therapy. | |
| | |
MedLine Citation:
|
PMID: 11389073 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Transduction of tumor cells with a cyclophosphamide (CPA)-activating cytochrome P-450 (P450) gene provides the capacity for localized prodrug activation and greatly sensitizes solid tumors to CPA treatment in vivo. The therapeutic impact of this P450-based cancer gene therapy strategy can be substantially enhanced by cotransduction of P450 reductase, a rate-limiting component of P450-dependent intratumoral CPA activation. The present study examined the possibility of further improving P450/P450 reductase-based gene therapy by using a novel schedule of CPA administration, involving repeated CPA injection every 6 days and previously shown to have an antiangiogenic component. 9L gliosarcoma cells transduced with the CPA-activating enzyme couple P450 2B6/P450 reductase and grown s.c. in immunodeficient severe combined immunodeficient (scid) mice were repeatedly challenged with 140 mg/kg CPA every 6 days. Full tumor regression leading to eradication of six of eight tumors was observed when the tumor size at the time of initial drug treatment was approximately 400 mm(3) (approximately 1.5% of body weight). Little or no overt toxicity of the repeated CPA treatment regimen was observed. The same CPA schedule was much less effective in inducing regression of 9L tumors that were not transduced with P450/P450 reductase. Repeated CPA treatment of mice bearing large, late-stage P450/P450 reductase-transduced tumors (approximately 9-16% of body weight) resulted in major (> or =95%) regression in 15 of 16 tumors, with tumor eradication observed in 2 cases. Although CPA resistance was found to emerge in the population of P450/P450 reductase-transduced tumors, this resistance primarily involved a loss of expression of the transduced P450 and/or P450 reductase gene, rather than development of intrinsic cellular resistance to the activated form of CPA. These findings demonstrate that repeated CPA treatment on a 6 day schedule can be highly effective when combined with P450/P450 reductase gene therapy and suggest that repeated transduction of tumors with prodrug-activation genes may be necessary to achieve tumor eradication and a sustained therapeutic response. |
| | |
Authors:
|
Y Jounaidi; D J Waxman |
Related Documents
:
|
17294333 - Evaluation of herpes simplex virus 1 thymidine kinase-mediated trapping of (131)i fiau ... 8521403 - Imaging the expression of transfected genes in vivo. 11377173 - Synthesis and cytotoxicity evaluation of novel indolylpyrimidines and indolylpyrazines ... |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: Cancer research Volume: 61 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2001 Jun |
Date Detail:
|
Created Date: 2001-06-04 Completed Date: 2001-06-21 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
|
Languages: eng Pagination: 4437-44 Citation Subset: IM |
Affiliation:
|
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Antineoplastic Agents, Alkylating / administration & dosage*, pharmacokinetics Biotransformation Brain Neoplasms / drug therapy, enzymology, genetics, therapy Combined Modality Therapy Cyclophosphamide / administration & dosage*, pharmacokinetics Cytochrome P-450 Enzyme System / genetics*, metabolism Dose-Response Relationship, Drug Drug Administration Schedule Gene Therapy / methods* Gliosarcoma / drug therapy, enzymology, genetics, therapy Humans Male Mice Mice, Inbred ICR NADPH-Ferrihemoprotein Reductase / genetics*, metabolism Rats Transduction, Genetic |
| Grant Support | |
ID/Acronym/Agency:
|
CA49248/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antineoplastic Agents, Alkylating; 50-18-0/Cyclophosphamide; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse ...
Next Document: Selective targeting to the hyperactive beta-catenin/T-cell factor pathway in colon cancer cells.