Date of Award

2010

Document type

Thesis

Degree Name

MSc by research (Master of Science by research)

First Supervisor

Dr Caoimhin Concannon

Second Supervisor

Professor Jochen Prehn

Keywords

Prostrate Neoplasms, Cell Death, Gossypol

Abstract

Cancer Biology

Tumourigenesis is a multistep process which includes the transformation of healthy cells into extremely malignant cells, caused by the disruption of normal tissue homeostasis. Hanahan and Weinberg propose that there are a common set of 'acquired capabilities' that most if not all cancers posses's in order to survive and proliferate despite changes in their normal cell physiology during cancer development (Hanahan and Weinberg, 2000). These "Hallmarks of Cancer", according to Hanahan and Weinberg, are the six essential physiological alterations which lead to malignant growth: self-sufficiency in growth signals, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis.

Evasion of apoptosis is a cleverly employed alteration by cancer to enhance their survival and proliferation. Most tumours have defective apoptotic machinery and for this reason therapies which are specifically targeted at promoting apoptosis are particularly effective in the treatment of cancer. This aspect of cancer biology will be the primary focus of this thesis.

Prostate cancer

It is estimated around 913,000 cases of prostate cancer were diagnosed worldwide in 2008. Of these, 338,000 cases were diagnosed in the EU with the highest incidence in Ireland (Ferlay et a/., 2008). Although there are several etiological factors (genetics, environment etc.) associated with prostate cancer, the most prominent risk factor is age with a rapid steep rise in incidences, more than any other cancer (Jemal eta/., 2003; Wang et a/., 2008).

There are several treatment options for prostate cancer including surgery, radiotherapy, hormone therapy and chemotherapy. Some patients can avail of surgery to remove the prostate-nerve sparing prostatectomy, but this is not option for every patient. Brachytherapy is another option which involves the placement of hundreds of radioactive seeds into the prostate. Ultrasound technology is used to ensure careful placement and to better control the effect on surrounding healthy tissue. The most common therapy for prostate cancer is Androgen Deprivation Therapy (ADT), as this cancer is highly reliant on androgens for proliferation (Miyamoto et a/., 2004). ADT can prolong patient's life expectancy, but nearly all patients progress to an androgen independent state which has no current effective therapy (Assikis and Simons, 2004).

In prostate cancer, chemotherapy is used to treat advanced cancers usually after radiotherapy or surgery have failed, or when the cancer progresses to a hormone refractory state and no longer responds to ADT. Docetaxel is one such chemotherapeutic drug used to treat advanced prostate cancer. Docetaxel is a member of the taxane class of drugs and acts by binding to microtubules causing them to become hyper-stabilized (Mollinedo and Gajate, 2003; Stein, 1999). This prevents depolymerisation of the microtubules, inhibiting mitotic cell division. It is cytotoxic to all quickly dividing cells including bone marrow and hair follicles as well as the cancer cells. Due to this extensive cytotoxicity which is not localised to cancer cells, there are adverse side effects associated with all chemotherapy, with alopecia being a very common side effect.

There is constant on-going research to develop new treatments that more specifically target cancer cells. This is likely to be a much more effective approach; it will try to limit the damage to surrounding healthy cells and help reduce the side effects associated with standard chemotherapy while still providing effective treatment to the patient. One of these promising new class of drugs currently in trials are the BH3 mimetics. They aim to promote apoptosis in cells with defective apoptotic machinery. These drugs will be discussed in more detail in section 1.4.

The Androgen Independent DU 145 prostate cancer cell line is one of the "classical" cell lines used to study prostate cancer (Alimirah et a/., 2006). It was originally derived from a 69 year old male with metastatic prostate cancer (Stone et a/., 1978). The DU 145 cell line completely lacks Bax expression.

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Comments

A thesis submitted for the degree of Masters of Science in Health Services Research, Royal College of Surgeons in Ireland, 2010.