| A concomitant ATP-depleting strategy markedly enhances anticancer agent activity. | |
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MedLine Citation:
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PMID: 11321035 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Most anticancer agents effect DNA damage which initiate the cell death pathways of necrosis and apoptosis, but cancer cells of lesser sensitivity are only sublethally injured, and recover. The two death pathways and their interelationships in the presence of endogenous inhibitors of apoptosis and genetic deletions that facilitates only sublethal damage, are reviewed. Both ATP and pyrimidine levels in the sublethally injured cancer cells are reduced but not to low levels insuffient to sustain cell viability. However, this sublethal damage by the anticancer agent creates a therapeutic opportunity for further reduction of these key metabolites to lower levels that will not support life. Data in tumor-bearing animals is reviewed demonstrating that a combination of ATP-depleting agents plus a de novo pyrimidine inhibitor (PALA) administered concomitantly with each of nine different anticancer agents markedly enhances tumor regression rates,and even produces some cures. It is necessary to deplete tumor ATP levels seveerely (>85%) by a combination of agents that block both synthesis (6-methylmercaptopurine riboside, a purine de novo synthesis inhibitor) and generation of ATP(6-aminonicotinamide, an inhibitor of glycolysis.) Cell viability cannot be sustained if the intracellular ATP level is reduced to 15% of normal or below. In vivo data employing this novel therapeutic strategy with cisplatin is presented. The potential significance of these findings to the improvement of cancer treatment is discussed. |
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Authors:
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D S Martin; D Spriggs; J A Koutcher |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Review |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: 6 ISSN: 1360-8185 ISO Abbreviation: Apoptosis Publication Date: 2001 Feb-Apr |
Date Detail:
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Created Date: 2001-04-25 Completed Date: 2001-09-06 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: United States |
Other Details:
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Languages: eng Pagination: 125-31 Citation Subset: IM |
Affiliation:
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Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate* Antineoplastic Agents / pharmacology*, therapeutic use Apoptosis / drug effects* Humans Neoplasms / drug therapy*, metabolism, pathology* |
| Grant Support | |
ID/Acronym/Agency:
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CA 25842/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 56-65-5/Adenosine Triphosphate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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