Differences Between Asymmetric cis and trans Platinum Complexes. Applications in Cancer Chemotherapy

Differences Between Asymmetric cis and trans Platinum Complexes.

Applications in Cancer Chemotherapy

Pantoja López, E.

Citation

Pantoja López, E. (2005, October 18). Differences Between Asymmetric cis and trans

Platinum Complexes. Applications in Cancer Chemotherapy. Retrieved from

https://hdl.handle.net/1887/3485

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the_{Institutional Repository of the University of Leiden} Downloaded from: https://hdl.handle.net/1887/3485

Stellingen (Propositions)

Differences between Asymmetric cis and trans Platinum Complexes.

Application in Cancer Chemotherapy.

1. Asymmetric trans-platinum(II) complexes are potential antitumor drugs, since they overcome cisplatin resistance.

[This thesis]

2. The formation of monofunctional lesions, structurally different from those observed with cisplatin, may be a required property for platinum(II) complexes with trans geometry to overcome cisplatin resistance.

[This thesis]

3. Many asymmetric cis-platinum(II) compounds are less cytotoxic than their trans analogues. This is an important feature for the search of new antitumor drugs, since it violates the original structure-activity relationship rules.

[This thesis]

4. It appears that the combination of aliphatic amines and planar N-donor ligands for the design of platinum compounds as antitumor drugs enhances the growth inhibition of cancer cells.

[This thesis]

5. The next step to develop platinum analogues will be the search for new drugs possessing sufficient oral bioavailability, as to be available to patients as tablets/capsules.

[L. R. Kelland et al. Journal of Inorganic Biochemistry 1999, 77, 111]

6. Reduced drug accumulation, inactivation by thiol containing species, increased repair/tolerance of platinum-DNA adducts, and alterations in proteins involved in apoptosis make different tumors to develop resistance to different platinum drugs. Resistance to cisplatin is a multifactorial process.

[M. A. Fuertes et al. Chemical Reviews 2003, 103, 645]

7. Genes encoding proteins, such as proteinases or other enzymes capable of disrupting tissues, and vascular permeability factors, are involved in carcinogenesis, and together with mutations in genes involved in DNA repair have to be taken into account in this complex disease. The effect of platinum antitumor drugs on these genes should be studied, as they may have an important role in encoding proteins.

[F. MacDonald, Molecular Biology of Cancer, 2nd Edition, 2004, Taylor & Francis] 8. The formation of ternary Pt-DNA-protein cross-links by platinum complexes

containing planar ligands, inducing protein-associated strand breaks, different from those of cisplatin, leads to an enhancement of their in vitro cytotoxicity.

9. The complete victory takes place when the army does not fight, the city is not besieged, the destruction does not extend for a long time, and in every case the enemy is conquered by the proper strategy and not by use of violence.

10. Life is what happens to you while you hope that something happens to you.