New approach to the activation of anti-cancer pro-drugs by metalloporphyrin-based cytochrome P450 mimics in all-aqueous biologically relevant system.
The low-molecular weight water-soluble Fe(III) and Mn(III) porphyrins--in biologically relevant phosphate-buffered saline medium with ascorbic acid as a source of electrons, under aerobic conditions but without co-oxidant - catalyze the hydroxylation of anti-cancer drug cyclophosphamide to active metabolite 4-hydroxycyclophosphamide in yields similar or higher than those typically obtained by the action of liver enzymes in vivo. The Fe(III) meso tetrakis(2,6-difluoro-3-sulfonatophenyl)porphyrin, highly electron-deficient at the metal site, was the most effective catalyst. If proven viable in vivo, this methodology could be expanded to localized or systemic activation of the entire family of oxazaphosphorine-based (and many other) anti-cancer drugs and become a powerful tool for an aggressive treatment of tumors with less toxic side effects to the patient.
Spasojević
Ivan
I
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. spaso001@mc.duke.edu <spaso001@mc.duke.edu>
Colvin
O Michael
OM
Warshany
Keith R
KR
Batinić-Haberle
Ines
I
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D003520:Cyclophosphamide / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006900:Hydroxylation; D008665:Metalloporphyrins / Q000737:chemistry*; D018716:Molecular Mimicry; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D011355:Prodrugs; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System