Novel platinum(II)-containing compounds as potent, mono- or combination therapies to combat resistance in GI cancers


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Katie Lloyd1, Emma Haynes1, Gabriele Wagner1
1University of Chester

Abstract

Background

In advanced GI cancers, the most commonly diagnosed stage, there is currently no standard first-line chemotherapy treatment. In the UK conventional treatments include platinum-containing compounds such as cisplatin, and its analogues oxaliplatin and carboplatin. However, their success is currently compromised due to severe dose-limiting, adverse effects such as nephrotoxicity, myelosuppression and neurotoxicity. Research has suggested that although two-thirds of patients with advanced gastrointestinal cancers respond to first-line chemotherapy, the majority develop drug resistance within a few months.

Method

Synthesis of novel platinum(II)-compounds was achieved by the addition of nitrones and the substitution of nitriles for hexamethylenetetramine or 7-nitro-1,3,5-triazaadamantane on PtCL2(nitrile)2. Crystal structures were then characterised by elemental analysis, infrared and NMR spectroscopy. Selected compounds were then validated in platinum-sensitive and platinum-resistance GI cell models. Dose and time dependent cellular and molecular effects were compared in current platinum and non-platinum containing chemotherapeutic drugs and novel platinum(II)-containing compounds.

Results

This data showed that new trans-configured platinum containing Compounds 5, 5a, 5c, 7a and 7c have a higher activity in cancer cell models compared to that of existing platinum containing and non-platinum containing compounds. Specifically, Compound 5 showed the highest anti-tumour activity IC50 9.6μM (±1.9μM) versus cisplatin IC50 44.8μM (±13.3μM). More importantly, these compounds are suggested to retain these anti-proliferative effects in platinum-resistant cell lines and cell cycle studies on Compound 5 showed an accumulation in sub-G1 phase rather than G2M phase (typically common for cisplatin).

Conclusion

Compounds 5a, 5c, 7a, 7c and specifically compound 5 have all shown promising anti-tumour and anti-proliferative activity, particularly in platinum-resistant cell lines. Increased potency of compounds compared with current chemotherapy drugs would result in lower doses for therapeutic effect; increasing patient compliance and reducing cytotoxicity. This highlights these compounds as potential alternative treatment agents for GI cancer, that could aid in combatting chemotherapeutic resistance associated with GI cancers.

Impact statement

The outcomes of this research should lead to increased awareness of the incidence and impact of resistance to first-line chemotherapy treatments on patients with GI cancers and could lead to better primary treatment options to increase response, quality of life and length of overall survival in those suffering with GI cancers.