Chemotherapy against cancer: a true solution?
Cancer arises when normal cells display uncontrolled growth and division, as a result they become tumour cells. These tumour cells can spread to other locations in the body via the blood or lymph. Normal cells in the body will grow and divide to produce more cells to maintain a healthy body. Apoptosis, or cell death, will occur when the cells are damaged or become old. However, this process can go wrong from time to time, when a damaged cell does not die, keeps growing and dividing, which can eventually lead to a tumour. Figure 1 depicts this process.
Cancer can be treated via radiation therapy, surgery, chemotherapy or a combination of these treatments. This paper will elaborate on the use, limitations and possible solutions of chemotherapy.
Chemotherapy is frequently applied for the treatment against certain types of cancer, in which anti-tumour drugs are used. These anti-tumour drugs contain a transition-metal with surrounding molecules, namely ligands. It is generally been accepted that the primarily target for anti-tumour drugs is the double stranded DNA (1)(2).
Cisplatin is the first and most routinely used anti-tumour drug in clinical practice, which is platinum (Pt) based drug. It has been stated, that the anti-tumour activity of cisplatin is due to an interaction between cisplatin and the DNA of the tumour cells. This interaction is a covalent binding between the cisplatin and the DNA base pairs, which occurs via ligand exchange from the transition-metal Pt with a DNA base pair. Figure 2 depicts this type of interaction. This interaction is only possible if the ligand is not tightly bounded to the transition-metal, so that it can rapidly exchange with the DNA base pair. When the anti-tumour drug is than bounded to the DNA base pair, it will inhibit further duplication of the DNA, thus it will inhibit the cell growth, which will lead to cell death.
However, the clinical utility of cisplatin is limited, because of side effects (1)(2). For instance, toxicity, which is caused by accumulation of the heavy metal Pt in the body, and drug resistance, towards certain cancer types. Unfortunately it is also possible that the anti-tumour drug also interact with normal cells, because distinction between tumour cells and normal cells can be very difficult, causing severe side effects for the patient. These side effects stimulated the search towards other transition-metal anti-tumour drugs, which display reduced toxicity and improved effectiveness.
An alternative transition-metal anti-tumour drug is a ruthenium (Ru) based drug, which display much lower toxicity. This is partly due to their ability to exploit the mechanisms of the body, which can transport iron, so they mimic iron binding and make use of this transport to reach the tumour cells.
It has been stated that the anti-tumour activity of the Ru drug is due to a covalent biding of Ru with a DNA base pair, analogously as cisplatin (see figure 2). Next to the covalent binding interaction, a second interaction with DNA is suggested. This second interaction is an intercalation of the Ru drug into a groove of the double stranded DNA, which occurs when the drug can slide into the DNA groove. Therefore the drug complex has to be more or less planar, otherwise it cannot fit into the groove. Figure 3 depicts this interaction. The intercalation will inhibit further cell growth, and eventually lead to cell death. However, this interaction is reversible (compared to the covalent binding interaction) and thus will be less aggressive than the first type .
One has to take into account that the precise mechanisms of these interactions described above are not been proved with certainty. So these explanations are just to give an likely understanding of how these interactions occur .
(1) Modifications of DNA by platinum complexes - Relation to resistance of tumors to platinum antitumor drugs - Viktor Brabec, Jana Kasparkova
(2) DNA binding mode of ruthenium complexes and relationship to tumour cell toxicity - Viktor Brabec, Olga Nováková