Diammine dicarboxylic acid platinum enhances cytotoxicity in platinum-resistant ovarian cancer cells through induction of apoptosis and S-phase cell arrest.
OBJECTIVE
Polysaccharides such as chondroitin play a potent role in tumor growth, tissue repair and angiogenesis. These properties make chondroitin a good candidate for novel drug delivery systems. Diammine dicarboxylic acid platinum (DDAP), a novel polymeric platinum compound, was developed by conjugating the platinum analogue to aspartate-chondroitin for drug delivery to tumor cells. DDAP improves platinum solubility which may reduce systemic toxicity and be more efficacious than cisplatin in killing tumor cells.


METHODS
We tested and compared the cytotoxic effects of DDAP and CDDP on the platinum-sensitive 2008 and A2780 ovarian cancer cell lines and their platinum-resistant sublines 2008.C13 and A2780cis; we also investigated DDAP's mechanism of action.


RESULTS
In the platinum-sensitive cell lines, the cytotoxic effects of DDAP and CDDP were comparable. However, in the platinum-resistant sublines, significantly greater cell-growth inhibition was induced by DDAP than by CDDP, especially at lower doses. DDAP also induced more apoptosis than CDDP did in the 2008.C13 subline, which was partially mediated by the caspase 3-dependent pathway. In addition, lower (but not higher) doses of DDAP arrested 90% of S-phase 2008.C13 cells, which might be associated with up-regulation of p21 and maintenance of low cyclin A expression. Furthermore, greater cellular uptake of DDAP was seen in platinum-resistant than in platinum-sensitive ovarian cancer cells.


CONCLUSIONS
Low-dose DDAP enhances drug delivery to platinum-resistant ovarian cancer cells and substantially inhibits their growth by inducting apoptosis and arresting cells in the S-phase, suggesting that DDAP may overcome platinum resistance in ovarian cancer.
Department of Gynecologic Oncology, Unit 1362, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, Houston, Texas 77030, USA.
Hong
H
Zheng
Wei
W
Hu
Dongfang
D
Yu
De-Yu
DY
Shen
Siqing
S
Fu
John J
JJ
Kavanagh
I-Chien
IC
Wei
David J
DJ
Yang
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002807:Chondroitin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D019925:Cyclin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D016196:S Phase / Q000187:drug effects*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D019925:Cyclin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009944:Organoplatinum Compounds; C532926:diammine dicarboxylic acid platinum; D001224:Aspartic Acid; D002807:Chondroitin; D002945:Cisplatin