OBJECTIVES: Therapeutic potential of conventionally used platinum-based drugs in treatment of colorectal tumours has been limited due to high incidence of tumour resistance to them and to their severe side effects. This evokes a search for more suitable anti-cancer drugs. We have compared ability of oxaliplatin and a novel platinum(IV) complex, LA-12, to modulate the cell cycle and induce apoptosis in human colon adenocarcinoma HCT116 wt and p53/p21 null cells, and have investigated molecular mechanisms involved. MATERIALS AND METHODS: Cell cycle-related changes were analysed by flow cytometry (bromodeoxyuridine/propidium iodide staining, histone H3 phosphorylation). Apoptosis was detected using flow cytometry (assays monitoring caspase activity) and fluorescence microscopy (nuclear morphology). Changes in levels of genes/proteins involved in cell cycle and apoptosis regulation were examined by RT-PCR and western blotting. RESULTS: Our results highlight the outstanding ability of LA-12 to induce effective elimination of colon cancer cells independently of p53/p21, and in significantly lower doses compared to oxaliplatin. While oxaliplatin induced p53- and p21-dependent G2 -phase arrest associated with downregulation of cyclin B1 and Cdk1, LA-12 allowed cells to enter M-phase of the cell cycle regardless of p53/p21 status. CONCLUSIONS: Higher malignant cell toxicity and ability to bypass cell cycle arrest important for the cell damage repair suggest LA-12 to be a more effective candidate for elimination of colon tumours from a variety of genetic backgrounds, compared with oxaliplatin.

• MeSH
• adenokarcinom farmakoterapie   genetika   MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčné dělení účinky léků   genetika   MeSH
• cyklin B1 genetika   MeSH
• HCT116 buňky MeSH
• inhibitor p21 cyklin-dependentní kinasy genetika   MeSH
• lidé MeSH
• mitóza účinky léků   genetika   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory tračníku farmakoterapie   genetika   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• oxaliplatin MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• cyklin B1 MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• oxaliplatin MeSH
• protinádorové látky MeSH

BACKGROUND: The initial pharmacokinetic study of a new anticancer agent (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum (IV) (LA-12) was complemented by proteomic screening of rat plasma. The objective of the study was to identify new LA-12 target proteins that serve as markers of LA-12 treatment, response and therapy monitoring. METHODS: Proteomic profiles were measured by surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS) in 72 samples of rat plasma randomized according to LA-12 dose and time from administration. Correlation of 92 peak clusters with platinum concentration was evaluated using Spearman correlation analysis. RESULTS: We identified Retinol-binding protein 4 (RBP4) whose level correlated with LA-12 level in treated rats. Similar results were observed in randomly selected patients involved in Phase I clinical trials. CONCLUSIONS: RBP4 induction is in agreement with known RBP4 regulation by amantadine and cisplatin. Since retinol metabolism is disrupted in many cancers and inversely associates with malignancy, these data identify a potential novel mechanism for the action of LA-12 and other similar anti-cancer drugs.

• Publikační typ
• časopisecké články MeSH