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Superior Efficacy of Phosphoplatins: Novel Non‐DNA‐Binding Platinum Drugs for Human Ovarian Cancer
Author(s) -
Moghaddas Shadi,
Majmudar Pooja,
Bose Rathindra N.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.527.2
Subject(s) - carboplatin , cisplatin , ovarian cancer , cytotoxicity , cancer research , in vivo , cancer cell , apoptosis , programmed cell death , pharmacology , clonogenic assay , toxicity , chemistry , cancer , biology , in vitro , chemotherapy , biochemistry , genetics , organic chemistry
Platinum (Pt) drugs are effectively used as cancer chemotherapy. These drugs form intra‐ and inter‐strand Pt‐DNA cross links leading to transcription inhibition process leading to cell death. Over 10% patients develop resistance to Pt drugs mainly due to the efficient removal of Pt from DNA by NER enzyme. The new class of Pt‐(II) and ‐(IV) pyrophosphato complexes developed in our laboratory, exhibit superior tumor‐specific toxicity and higher efficacy in human ovarian cancer (HOC) in vivo and head and neck cancer cell lines in vitro . Their mechanism of cytotoxicity does not involve covalent binding of Pt to DNA, but rather activate the Fas receptor signaling pathway leading to cell death. Clonogenic assay demonstrated that the phosphoplatins are more effective towards both cisplatin (CP)‐sensitive and ‐resistant HOC cell lines at lower concentrations as compared to CP and carboplatin (CR). In vivo studies in SCID mice, exhibit superior tumor regression and reduced toxicity of HOC compared to CP and CR. Apoptosis was established as the primary mechanism of cytotoxicity by cell cycle analysis and induced by activating cell‐surface receptors genes targeted towards cancer cells. Superior pharmacokinetic properties, reduced toxicity, better efficacy, ability to overcome CP‐resistant and activation of apoptotic genes make phosphaplatins the promising next generation of anticancer drugs.