In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C93-C93
Abstract:
Background: Oxaliplatin has unique activity against colon cancer cells distinctly different from cisplatin. Aim of this study was to determine the anticancer properties of new mono-substituted oxaliplatin analogs, namely KP1537 and KP1691, to define the underlying cellular and molecular mechanisms. Methods: Cytotoxic/antiproliferative effects were tested against selected human cancer cell lines by MTT analysis. The impact of the DNA damage response pathway on the drug activities were determined using HCT-116 human colon carcinoma cells together with p53 or p21/WAF1 deleted sublines. Furthermore, DNA damage, cell cycle distribution and induction of apoptosis were analysed by Western Blotting, FACS analysis and immunofluorescence. Platinum accumulation was determined by ICP-MS. For in vivo toxicity experiments, mice were treated with KP1691 and oxaliplatin. Results: Both oxaliplatin analogues had IC50 values in the low µM range, with those for KP1691 being significantly lower in comparison to oxaliplatin. Additionally, KP1691 was less affected by the p53 status of the cells as compared to oxaliplatin. The new compounds were more rapidly taken up by the tumor cells and accumulated over time to higher intracellular concentrations as compared to oxaliplatin. In HCT-116 cells all platinum drugs inhibited the DNA synthesis in a p53-dependent manner, associated with a distinct induction of p53 and p21 in the HCT-116 p53 cell model. This suggests that inhibition of DNA replication due to platinum adducts leads to a p53-dependent cell cycle arrest. KP1537 and KP1691 induced potent G1/S and G2/M arrests in parental HCT-116. While at wild-type p53 conditions the platinum drugs resulted in almost complete loss of S-phase, this fraction was widely unchanged in the p53- deleted subline. Accordingly, expression of cellcycle related genes including cyclin A, cyclin B1, and CDK1 were down-regulated in a p53-dependent manner. Platinum drug-induced DNA damage was confirmed by the phosphorylation of H2AX. First in vivo toxicity experiments in mice indicated significantly less side effects (weight loss) after KP1691 than after oxaliplatin treatment. Conclusion: Taken together, these findings suggest that KP1537 and KP1691 have promising anticancer properties in vitro. Several aspects, including the lower IC50 values, higher accumulation rates and less side effects of KP1537 and KP1691 as compared to the parental compound oxaliplatin, suggest them for further (pre-) clinical development. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C93.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-C93
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2062135-8
SSG:
12
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