The focus of our research and this thesis was to investigate how statins are able to influence colorectal cancer formation and whether they might be used as a chemopreventive or adjuvant... Show moreThe focus of our research and this thesis was to investigate how statins are able to influence colorectal cancer formation and whether they might be used as a chemopreventive or adjuvant therapeutic agent in colorectal cancer. As we have shown, statins are able to influence colorectal cancer cells at different levels from the level of BMP receptor expression and receptor cycling, effects on the entire kinome in cancer cells, to epigenetic changes via its ability to alter gene promoter methylation. Our results suggest that statins could provide an interesting and favorable option for use in a chemopreventive or adjuvant setting. There are however aspects which have to be assessed before a drug is used for chemoprevention. The risk/benefit ratio should be assessed carefully, especially when administered to healthy individuals. Ideally, a chemopreventive agent should fulfill certain criteria. Most importantly, the drug must be effective and exhibit minimal side-effects. The safety profile of a drug and efficacy varies significantly between patients and is dependent on disease severity. Therefore, it is of great importance to critically assess the possible benefits of chemoprevention in comparison to the risk and inconvenience that could come with it. In the general population the lifetime risk of CRC is 5 % and the number needed to treat to prevent one CRC death will be very high. In patients at average risk, compliance in this asymptomatic cohort outside a study is likely to be low. The balance of risk versus benefit is more in favor of its use in high risk groups such as individuals especially susceptible to colorectal cancer because of environmental risk factors (diet high in animal protein and fat), patients with inflammatory bowel disease (IBD) and those with a hereditary predisposition to CRC. These include patients with Familial Adenomatous Polyposis (FAP), Lynch Syndrome, Hereditary Non Polyposis Colon Carcinoma (HNPCC) and patients with a previous history of colorectal or adenomatous polyps. However, effective chemoprevention within one high risk group does not mean that the same chemoprevention is suitable for all groups. This stems from and also illustrates the fact that CRC is not one disease but a heterogeneous group of diseases with different underlying molecular mechanisms. Statins have an excellent safety profile, have been use for decades and have a beneficial effect on cardiovascular disease risk even in healthy individuals. Next to this we have shown that the use of statins has strong protective effect on the development of colorectal cancer expressing SMAD4 and does not increase the risk of developing CRC in SMAD4 negative tumors. Taken together our results suggest that statins could present a very interesting and favorable agent for use in a chemopreventive or adjuvant setting in CRC. Show less
One of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic... Show moreOne of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic resistance. Limitations of chemotherapy have led to the exploration of alternative anti-cancer approaches in order to improve efficacy, such as chemoprevention. Chemopreventive agents interfere with rate limiting steps in tumor progression, such as for example the establishment of a functional tumor vasculature. Currently, there is a large and unfolding picture of rate-limiting steps during tumor progression which can provide us with numerous potential therapeutic targets, where it is becoming increasingly clear both the tumor itself as its microenvironment contribute in these steps. Current research focuses on exploring chemopreventive approaches as part of combination strategies. One of the most investigated approaches in these combinational strategies is targeting the tumor with chemotherapy together with chemopreventive agents. This thesis explores the use of chemopreventive approaches as monotherapy and in combinational approaches with chemotherapy and explores and discusses their effects on both the tumor as the tumor__s microenvironment. It shows that these combinational approaches hold great promise, if taking both the tumor as the tumor__s microenvironment into account as therapeutic targets. Show less
Cutaneous melanoma is the most aggressive form of skin cancer and its incidence among Caucasian populations has increased whereas mortality rates are stabilizing or decreasing. The total burden of... Show moreCutaneous melanoma is the most aggressive form of skin cancer and its incidence among Caucasian populations has increased whereas mortality rates are stabilizing or decreasing. The total burden of melanoma is expected to be increasing. As effective treatment options for advanced melanoma are lacking, melanoma prevention may be the key issue in melanoma disease control. Although sun protection programs have increased awareness, they have not resulted in a decreased melanoma incidence. In addition, most melanoma risk factors are not amenable. Alternative approaches such as cancer chemoprevention are, therefore, important research topics. Several agents, such as statins, non-steroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors, have been claimed to have chemopreventive properties. However, it is unknown which of these have the best potential to be useful. This thesis presents: - epidemiologic cancer registry-based studies from The Netherlands on the epidemiology of extracutaneous melanoma and on the burden of disease due to cutaneous melanoma - a qualitative review discussing candidate drugs for melanoma chemoprevention, their possible mechanisms of action, and evidence for their chemopreventive efficacy, safety and tolerability - pharmacoepidemiological studies testing hypotheses on chemopreventive activityof several drugs on melanoma - pharmacoepidemiological studies on the association between estrogen use and melanoma. Show less
