How Therapies Are Being Rationally Designed Biology Essay

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Cancer is a group of diseases characterized by unregulated cell growth and the spread of cells from their site of origin. The earliest therapeutic strategy used against cancer was to surgically remove as much cancer as possible. This strategy was shown to not be a precise procedure. Therefore chemotherapy and radiotherapy have been use to slow the growth of metastasized cells. The purposes of cancer therapy are to prevent the production and to kill the cancer cells. With all drugs the aim is to achieve an effective result with the minimum side-effects. There are many therapies to treat cancer but the two mentioned in this essay are CDK inhibitors and Vascular targeting.

Small molecule cyclin-dependant kinase inhibitors are being developed as therapeutic agents. The cell cycle progression is regulated by cyclin-dependant kinases (CDKs). CDKs are expressed throughout the cell; whereas cyclin levels are controlled by transcriptional regulation of cyclin-encoding genes .CDKs are a family of serine/threonine kinases that during the G1 phase phosphorylate the retinoblastoma (Rb) protein. In human cancer, the Rb pathway regularly is non-functional. Only a few human tumours contain a mutation of the Rb gene, the majority of human malignancies distort the Rb function this is due to the hyperactivation of CDKs and the increase in CDK and the cofactors (cyclin).(1) Therefore CDKs are suitable targets for cancer therapy. Many properties are being designed to interfere with CDK activation. An effective inhibition of CDK activity has been found from rationally designed small inhibitors. The loss of cell-cycle checkpoints is a main feature of human cancers. Alterations in the components of the cell cycle and checkpoint pathways in most tumours leads to the deregulation of oncogenes and tumour suppressors, which has important suggestions for the current therapeutic regimens and cell cycle targets. Preclinical studies have shown and indicated that cells with defective checkpoint functions are more vulnerable to anticancer agents. Therefore research is focused on identifying compounds that disrupt the cell cycle checkpoints. The following have been focused: the development of chemical inhibitors, rational drug design, and the strategy of genetic based screening technologies to identify anticancer therapies. The activity of CDKs is mostly deregulated in tumours therefore compounds that slow down the CDK function might be effective anticancer agents. CDK inhibition is thought to block tumour growth. Small molecule inhibitors that target CDK1 cause a G2 arrest in human cells. It was found out the inhibition of CDK1 in cells that overexpress MYC led to apoptosis. The slowdown in CDK1 induced apoptosis is exact for MYC transformation as cells transformed by ocogenes could be captured in G2 phase without the induction of apoptosis. Survivin is a substrate of CDK1 a mediator of the apoptotic response to CDK inhibition. Results show the inhibition of CDK1 may value in the treatment of human tumours that over express MYC. A cell that over expressed MYC is sensitive to surviving inhibition this suggests it is an ideal target for small-molecule surviving inhibitors (3). Molecular targeting therapies for cancer provide selective killing of tumour cells whereas targeted therapy require the oncogenic pathways to be activated in the tumour cells. An effective inhibition of CDK activity has been found from rationally designed small inhibitors such as Flavopiridol which acts as a competitive inhibitor of all CDKs tested by targeting its ATP-binding sites this can be seen in figure 1 which shows where in the cell cycle this inhibitor acts. It is shown this cyclin dependant kinase inhibitor has effective antiproliferative activity in many cancer cell lines. Studies in mouse tumours have shown this inhibitor acts synergistically with other anticancer agents. Flavopiridol produced positive clinical responses in phase 1 and 2 studies of many cancer types and current clinical trials are assessing the drug in breast and prostate cancers.(2) The clinical tests of this inhibitor and CDK1s have generated further research effects to CDK1S through the manipulation of the phosphorylation and cyclin-binding sites of CDK proteins. Trials showed the specificity of CDK1s still remains a limiting factor this is because the patients tested in phase 1 and 2 experienced severe side-effects. Further studies on Flavopiridol have suggested this inhibitor acts through cell-cycle independent mechanisms because it binds and activates to cytosolic aldehyde dehydrogenase and glycogen phosphorylse and inhibits transcription.(2) Further studies will determine the specificity of an inhibitor and identify targets that might be helpful or antagonistic to therapeutic strategies with newly developed compounds. Flavopiridol is the first cdk inhibitor tested in clinical trials. Many questions still remain to be answered however a positive experience will encourage the development of novel cdk inhibitors for cancer therapy.(1)(2)(3)(4)

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Figure 1 explains the stages of the cell cycle where the cyclin dependant kinases are regulated. This figure shows the where in the cycle Flavopiridol acts.(1)

Many methods to cancer therapy have mainly been determined on achieving increased tumour cell kill. Recently another treatment approach has been considered. Cancer therapies mainly target the neoplastic cell population directly, this technique actions to damage the tumour’s nutritional support system by targeting the tumour blood vessel network. Vascular targeting moves are based in the recognition that a continuously expanding vasculature is an essential requirement for tumour initiation, progression and metastasis.(5) These vascular agents are different from the conventional anticancer treatments such as radiation therapy. Tumour endothelium represents a main target for cancer therapy because of its role in tumour survival, progression and spread. It has been shown that strategies directed against the tumour blood vessel network may offer therapeutic opportunities as well as enhancing the efficacies of conventional anticancer treatments. Vascular-targeting therapies fall into two categories whether they interfere with new blood vessel development or damage the tumour vasculature. The first aim is to slow the tumour- initiated angiogenic process. Angiogenesis inhibitors (AI) look to interrupt essential parts of angiogenesis such as the signalling between tumour, endothelial and stromal cells, and also the function of endothelial in order to prevent new blood formation.(5) The schemes that have been tested include the use of drugs that interfere with the release or export of antiogenic stimuli, antibodies to inhibit or inactivate angiogenic factors after their release, drugs that slow the action of receptors, and inhibitors of invasion and agents that that inhibit the proliferation in endothelial cells. Most of these agents are undergoing clinical evaluations. Another approach involves the destruction of the tumour vessel network. Vascular- distrupting agents (VDAs) cause a rapid and selective vascular shutdown in tumours producing secondary tumour cell death due to ischemia.(5) The disruption of a single tumour blood vessel causes the effect of starving and killing the tumour cells making this a very effective therapeutic strategy. However the prevalence of ischemia in clinical trials of systemically administered VDAs targeting the colchinebinding site of tublin suggests the therapeutic value is settled by intrinsic systemic toxicity. Ideas have been focused on improving the therapeutic index of VDAs and improving tumour selectivity. Matrix metalloproteinases (MMP) are a family of 24 zinc-dependant endopeptidases with a role in tumour progression. MMPs also play a role in controlling the tumour cell growth, migration, and metastasis. The MMP family comprise of two groups, the membrane-type MMPs(MT-MMPs) that are further sub classed by a transmembrane domain(MT1,2,3,and5) or by glycophosphatidylinsitol anchor(MT4 and 6). MT1-MMP is a widely studied member that plays a role in tumorigenesis. The role in MT1-MMP in tumour expansion and progression and the elevated expression in a wide range of tumours support its potential as a target for therapeutic use in cancer. To improve the therapeutic index of VDAs an active form of VDA is released from an inactive form within the tumour microenvironment by using the increased activity of MMPs. A novel agent (ICT2588) was developed which is selectively metabolized by MT1-MMP to release an active VDA (ICT2552). The activation of ICT2558 in the tumour showed undetectable levels of active ICT2552 in normal tissues in VIVO this level led to a greater therapeutic index. In addition the coadminstration of ICT2588 with chemotherapeutic agent doxorubicin resulted in enhanced antitumor effect and cures in tumours in preclinical studies.(6)(7)

Vasculature targeting is a therapeutic approach intended to destroy the neovasculature in order to starve the tumour of oxygen and lead to the weakening of tumours. Small molecule VDAs have shown to have specific targeting of the tumour vascular system. Further clinical trials in the future will enable theses agents to reach cancer patients either as single agents or as a combination therapy. Cyclin dependent kinases are overexpressed and amplified in some cancers, making them possible molecular targets for cancer therapies. An effective inhibition of CDK activity has been found from rationally designed small inhibitors such as Flavopiridol. Flavopiridol was the first inhibitor to be tested in clinical trails however failed to demonstrate clinical activity in phases I and II. However, investigations into combining the inhibitor with existing chemotherapeutic agents are ongoing. It has been shown it’s rational to develop drugs that target specific cancer hallmarks, rather than generic drugs and treatments like chemotherapy or radiotherapy.

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