期刊
ACS CHEMICAL BIOLOGY
卷 12, 期 4, 页码 933-946出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.7b00023
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资金
- National Institutes of Health [CA 55791]
- Roswell Park Cancer Support Grant [P30CA016056]
- research supplement to promote diversity in health related research [CA 55791S]
The tetrapyrrole structure of porphyrins used as. photosentizing agents is thought to:determine uptake, and retention by malignant epithelial cancer cells. To assess the contribution, of the oxidized state of individual rings to. these cellular processes, bacteriochlorophyll a was converted into the ring D reduced 3-deviny1-3- [1-(1-,bexyloxy)ethy1] pyropheophorbide-a (HPPH) and the corresponding ring B reduced isomer (iso-HPPH). The carboxylic acid,analogs of both ring B.and ring D reduced isomers showed Several fold higher: accumulatiOn into the mitochondria and endoplasmie' reticulum,by primary culture of human lung and head and heck cancer, cells than the corresponding, methyl ester analogs that localize, primarily to granular vesicles and, to a lesser extent to mitochondria. However, long-term cellular retention of these cornpounds exhibited an inverse relationship, With tumor cells: generally retaining better the methyl-ester derivatives: In vivo distribution and tumor uptake was evaluated in the model of BALB/c mice bearing Colon26 tumors using the respective C-14-labeled analogs. Both carboxylic acid derivatives demonstrated Similar intracellular localization and long, term tumor cure with no: significant skin phototoxicity. PDT-mediated tumor action involved vascular damage; which was, confirmed a reduction in blood flow and immunohistochemical assessment of damage to the vascular endothelium. The HPPH stereoisomers (epimers), showed identical uptake vitro & in vivo)intracellular retention and photpreaction.
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