Lani
01-23-2008, 09:27 AM
compound
Light powered platinum more targeted & 80 times more powerful than similar cancer treatments [University of Warwick]
Researchers from the Universities of Warwick, Edinburgh, Dundee and the Czech Republic's Institute of Biophysics have discovered a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use "light activation" to kill cancer cells in much more targeted way than similar treatments.
The platinum-based compound known as "trans, trans, trans- [Pt(N3)2(OH)2(NH3)(py)]", or a light activated PtIV complex, is highly stable and non-toxic if left in the dark but if light falls upon it becomes much less stable and highly toxic to cancer cells. In fact it is between 13 and 80 times more toxic (depending on how and on which cells it is used) to cancer cells than the current platinum based anti-cancer drug Cisplatin. Moreover it kills the cells by a different mechanism of action, so it can also kill cisplatin-resistant cells.
Professor Peter Sadler, Chairman of the Chemistry Department of the University of Warwick, who led the research project said:
"Light activation provides its massive toxic power and also allows treatment to be targeted much more accurately against cancer cells."
The compound could be used in particular to treat surface cancers. Patients could be treated in a darkened environment with light directed specifically at cancer cells containing the compound activating the compound's toxicity and killing those cells. Normal cells exposed to the compound would be protected by keeping the patient in darkness until the compound has passed through and out of the patient.
The new light activated PtIV complex is also more efficient in its toxic action on cancer cells in that, unlike other compounds currently used in photodynamic therapy, it does not require the presence of significant amounts of oxygen within a cancer cell to become toxic. Cancer cells tend to have less oxygen present than normal cells.
Although this work is in its early stages, the researches are hopeful that, in a few years time, the new platinum compound could be used in a new type of photoactivated chemotherapy for cancer.
ABSTRACT: A potent cytotoxic photoactivated platinum complex [Proceedings of the National Academy of Sciencese]
We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(py)] (1) contains an octahedral PtIV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the PtII anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine PtII adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido PtIV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.
Light powered platinum more targeted & 80 times more powerful than similar cancer treatments [University of Warwick]
Researchers from the Universities of Warwick, Edinburgh, Dundee and the Czech Republic's Institute of Biophysics have discovered a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use "light activation" to kill cancer cells in much more targeted way than similar treatments.
The platinum-based compound known as "trans, trans, trans- [Pt(N3)2(OH)2(NH3)(py)]", or a light activated PtIV complex, is highly stable and non-toxic if left in the dark but if light falls upon it becomes much less stable and highly toxic to cancer cells. In fact it is between 13 and 80 times more toxic (depending on how and on which cells it is used) to cancer cells than the current platinum based anti-cancer drug Cisplatin. Moreover it kills the cells by a different mechanism of action, so it can also kill cisplatin-resistant cells.
Professor Peter Sadler, Chairman of the Chemistry Department of the University of Warwick, who led the research project said:
"Light activation provides its massive toxic power and also allows treatment to be targeted much more accurately against cancer cells."
The compound could be used in particular to treat surface cancers. Patients could be treated in a darkened environment with light directed specifically at cancer cells containing the compound activating the compound's toxicity and killing those cells. Normal cells exposed to the compound would be protected by keeping the patient in darkness until the compound has passed through and out of the patient.
The new light activated PtIV complex is also more efficient in its toxic action on cancer cells in that, unlike other compounds currently used in photodynamic therapy, it does not require the presence of significant amounts of oxygen within a cancer cell to become toxic. Cancer cells tend to have less oxygen present than normal cells.
Although this work is in its early stages, the researches are hopeful that, in a few years time, the new platinum compound could be used in a new type of photoactivated chemotherapy for cancer.
ABSTRACT: A potent cytotoxic photoactivated platinum complex [Proceedings of the National Academy of Sciencese]
We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(py)] (1) contains an octahedral PtIV center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the PtII anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine PtII adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido PtIV complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.