Cancer is uncontrolled cell division due to a large number of genetic mutations (DNA damage). The cell cycle has different phases, and the chemotherapy drugs cover and aim at the different stages of cell cycle regulation (Figure 1).
Figure 1: Cell Cycle Phases
The ambition of the chemotherapy is to interrupt or at least reduce the proliferation of the cancer cells by destroying them, preventing anarchic cell division within the body and proliferation to other parts of the body.
In this review, the mechanism of a selection of chemotherapy drugs are reviewed, as well as the importance of their toxicity level in treating cancer.
Xie and al. have investigated the effect of cyclophosphamide on gene expression of hepatic cytochrome P 450 1B1 and ï¢-actin in the human hematopoietic promyelocytic leukaemia cell line HP-60S and its multidrug-resistant phenotype HL-60R, and the eventual cytotoxicity generated by the presence of cyclophophamide. They have shown that the expression of both CYP1B1 and ï¢-actin was decreased after exposure. So not only under constant exposure to CPA, CYTP1B1 gene expression is decreased, but the lower level of ï¢-actin seem to be implicated in the cytoxicity of CPA.
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STI-571 is the first protein kinase inhibitor of BCR-ABL to be allowed for CML treatment. Schindler et al. have decided to work out the crystal structure of the catalytic site of the Bcr-Abl protein and a derivative of Gleevec inhibitor to understand the mechanism lying behind the inhibition of Bcr-Abl tyrosine kinase domain. Their finding suggests that STI-571 can make use of these three-dimensional structure difference involving inactive and active forms and also the dissimilarities within the inactive structures of tyrosine kinases, to selectively bind on inactive Abl structure. This study suggests that if a good clinical diagnosis is made, we can specifically target a unique survival-promoting tyrosine kinase and limit cytotoxicity resulting from the action of STI-571 to other normal cells.
ACTIVATION OF p53 PATHWAY
Vassilev and al. have studied the re-activation of the p53 pathway by inhibiting the action of MDM2 using small molecule antagonist of MDM2. They also used X-ray crystallography to determine the three-dimensional structure and investigate the mechanism of binding. They demonstrated that by inhibiting the MDM2-p53 interaction by Nutlins, the intranuclear concentration of p5 is increased, in return has a positive regulation of mdm2 gene and as result the activation of the p53 involved in apoptosis, but only in cells wild type phenotype p53 (and not heterozygote p53 cells, that loose cell death function).
INHIBITOR OF TOPOISOMERASE
Hajji et al. study is based on the anthracylcine aclarubicin (ACLA, aka Aclacinomycin®), which is an intercalative agent. This compound intercalates itself between the double strands of the DNA helix as a consequence it inhibits the synthesis of the nucleic acids. In this study Hajii et al. wanted to know whether this compound is efficient as of its capability to set off DNA damage (no religation) or because it targets an enzyme which is essential for replication (topoisomerases I and II), hence mitosis. This study suggests that the toxic effect of ACLA on topoisomerase I seem to provoke DNA damages and potential growth inhibition (due to reduce protein production). This is possibly responsible for cell cycle arrest or apoptosis. this finding shows potential, as ACLA seems to have a double action. It reduces the action of topoisomerase I as well as of topoisomerase II, important enzymes in the initiation of DNA replication and DNA reparation essentially.
Taxol® is a natural product from the Yew tree, which stimulates polymerisation, but it also prevents disassembly of microtubules into tubulins. Hence, it cqn deregulate the dynamic equilibrium between polymerisation (microtubules) and depolymerisation (tubulin: subunit of microtubules) essential during mitosis. Johnson et al. wanted to know whether the anti-mitotic property of paclitaxel (Taxol®) induced the apoptosis or if the two were not correlated. Their results suggest that the apoptotic attribute of paclitaxel is not associated with its anti-mitotic attribute. However, they have found out that 5-fluorouracil upsets the cytoxicity effect of paclitaxel, preventing the cancer cells form entering G2/M phase to undergo apoptosis. It implies that both drugs should not be combined to treat cancer, as both combined achieve smaller cytotoxic result than their additive [. Once more, it reveals how important is a drug's cytotoxic attribute, and how a combinatory treatment might affect it.
CHEMOPREVENTIVE: NO SIDE EFFECTS
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Cancer chemoprevention is defined as the use of natural products that would reduce the risk, stop or reverse the process of carcinogenesis . Resveratrol is one of them. It is a well-known stilbenoid found in grapes, which has shown cancer prevention properties . Lee et al., have synthesized a derivatives of stilbenoids and prolonged testings on 3,4,5-trimethoxy-4-bromo-cis-stillbene (BCS), which has showed potential growth inhibitory. BCS has then undergone a series of investigation to determine whether it is a potential cancer chemopreventive drug or not. BCS appeared to be an excellent growth inhibitor and apoptosis inducer in A549 lung cancer cells.
Unfortunately, the different literature reviews show that chemotherapies are powerful treatments, which have an effect upon the whole body. A chemotherapy drug can never be efficient without some risks of toxicity. Toxicity is a necessity in order to fight against cancers. The treatment used has to be strong but its drawbacks are in most of the cases proportional to it. There is no small chemotherapy, without any side effects. Side effects are huge efforts made to fight against the deadly effects of cancer, but again their side effects can be reduced using the knowledge obtained so far on both cancer cells and normal cells. The only outcome that can be reduced is the potential cytotoxicity of these drugs to normal cells