Principles Of Cyclotheropy

Cancer was first known as an ancient condition by the early Epyptians. It is a collection of disease with the common feature of uncontrolled growth. It is initiated in a single cell which then multiplies and acquires additional changes that give it a survival advantage over its neighbors. The altered cells further then generate billions of cells to become a cancer.
Current treatment of cancer includes surgery, chemotherapy, hormone therapy, radiotherapy, immunotherapy and photodynamic therapy ect. However, Chemotherapy remains the main form of drug treatment at all stages of cancer development. Its action is largely base on against rapidly dividing cells effectively. In order to block cell proliferation, chemotherapy involves chemicals to disrupt the cell cycle directly which targets RNA, DNA and protein molecules. As it targets rapidly dividing cells, chemotherapeutic drugs could also affect normal cells and causes some side-effects. Patients suffer from bone marrow suppressinon, neuropenia, anemia, nausea and vomiting, amongst other ailments. In addition, they are subjected to an increased risk of developing second tumors later in life.
In order to avoid the side effects of chemotherapy in normal cell, an therapeautic strategy is suggested currently, Cyclotherapy. This concept highlights that as cytotoxic drugs specifically target on cycling cell, as such the normal cells are able to be protected by inducing a transient cell cycle arrest. Cyclotherapy works especially in TP53 mutated tumor suppressor. The p53 gene is located on the short arm of chromosome 17 also known as 'the Guardian of the Genome' (lane,1992) In normal cells, the content of p53 will be induced if there is a genotoxin damage such as ionizing radiation. It blocks cell cycle progression until repair is completed. In cancerous cells the defective P53 does not block proliferation as such damage accumulates in daughter cells. If the damaged cell could not be repaired it will then go through the process of apoptosis.( Blagosklonny et al,2001)
Figure 1. Principles of cyclotheropy

In recent publications, there are a series of cyclotherapy regimes have being investigated. Those p53 activator included: nulin-3,??low doses of dactinomycin(LdactD),?? tenovin-6??,leptomycin?? B ect. The find out includes:

Induces reversible cytostatic effect in cells culture and further on protect cells from cytotoxic chemotherapy drugs.
Dominique Kranz and Matthias Dobelstein assessed whether nutlin-3-induced p53 activation is reversible in this system. They applied nutlin-3 and gemcitabine treatment in U2OS cell which from osteosarcoma. To the end, nutlin-3 was removed after treating cells for 24 hours, and the levels of p53 and its target gene products were monitored by immunoblot analysis in a time course. The result showed that the accumulation of Mdm2 and p21 diminished at 3 hours after nutlin-3 was removaled and was completely abolished after 6 hours. These observations suggest that cells are able to resume the cell proliferation on withdrawal of nutlin-3.
Fig 2. p53 levels and activity after removal of nutlin-3.

Actinomycin D(Act D) is an old chemotherapy agent and had been used in the clinic for the treatment of children with rhabdomyosarcoma, wilm's tumor and Hodgkin' disease. Bhavya Rao al et exam breast cancer and colon carcinoma cell for reversibility of the cell proliferation after removed ActD treatment for 6 days. The results of this experiment show that there is an increase of cell culture after remove ActD clearly.
Fig. 3. Recovery after remove VX-680 treatment, ActD treatment and LDactD/VX-680 treatment for 8 days in fresh medium.

The protective effect from these p53 activators are actually dependent on the presence of WT p53 (wild type p53).
Among some systematic analysis showed that Nutlin-3 is most promising chemoprotectant overall. It shows good and highly-selective protection of normal cells from each anticancer drug tested.
The small-molecule nutlin-3 was developed to inhibit the p53 antagonist Mdm2, thereby prevents cells from multiplying damaged DNA via the production of P21, which interacts with a cell division-stimulating protein(cdk2). With p21 bound to cdk2,a cell can't pass through to the next phase of the cell cycle. In the absence of unctional p53, P21 protein is not increased and can't act as the 'stop signal' for cell division.
Fig 4. effect of nut levels and activity in HCT116p53wt and HCT116 p53-/- cells

Further more, Chih- Shou Chen proved that LActD will also achieve cell cycle arrest for cell protection. Low dose of actinomycin D (LActD) causes ribosomal stress, which decreases MDM2 activity, resulting in p 53 stabilization and activation. ActD can thus be used for p53-based cyclotherapy.(3)
However, Actinamycin D was evaluated by Bhavya Rao whether there is difference in the p53 response after treatment with Nutlin-3 and LActD. The study found out despite the function of LActD is similar to Nutlin-3 as it is able to increase effectively p53 levels and arrest cell cycle in the cell with wild-type p53. Their mechanisms of action are different. Nutlin-3 binds directly to mdm2, whereas ActD disrupting ribosomal RNA biosynthesis in order to requests sufficient molecules of ribosomal proteins to inhibit mdm2. Perhaps this is the reason AtcD's treatment has a much longer process than Nutlin-3 treatment which directly inhibiting mdm2 to increases p53 levels in the same experiment.
Fig 5.

Also p53-based cyclotherapy has been proved in many studies by testing in different carcinoma cells. It may be fail to induce irreversible growth arrest in epithelial cancer cells.(Baoying Huang, 2009). In this study they study the role of p53 activation in irreversible growth arrest using a panel of eight epithelial cancer cell lines and primary epithelial cells, which include a second lung cancer line,two colon cancer line(HCT116) and RKO, two prostate LnCaP and 22Rv1; two osossarcoma cell lines(SJSA1 and MHM); one breast (MCF7), one melanoma(LOX) and one renal cancer line(A498). These 8 epithelial cancer cell lines was exposed to nutlin-3a for 6 days and their ability to proliferate was assessed after several days of growth. When proliferative potential was measured by total cell count, 3 days after nutlin-3a removal, only the six cell lines that partially recovered their clonogenic growth(H460, A549, Lox ,22Rv1, A498 and HCT116). However RKO and MCF7 cells did not re-enter proliferation as p53 remained as high as in the presence of nutlin-3a up to 3 days after its removal. These experiments indicated that some cancer cell lines can reverse their senescence-like phenotype and resume proliferation while others maintain continuous cell cycle arrest in the absence of nutlin-3a.
Fig 6. colonogenic growth of cancer cells before and after nutlin-3a treatment

Future Direction
The cyclotheray priniciple needs to be validated not only in vitro but also in vivo. All these chemoprotectans need to be further indentified in future research in order to find out the most suitable compound. Even the optimal cyclotherpy regimes may make different result in different patient, as such more cell culture studies need to be conducted. More over, the optimal cyclotherpy regimes should make sure the it would not activate cell cycle arrest in tumor cells. Time consuming of clinical approval of potential chemoprotectants is also one of the biggest challenge. Currently Nutlin-like compound is still undergoing phase 1 clinical trial and Tenovin-6 is still under preclinical investigation.

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