Department of Medical Imaging and Clinical Oncology

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Browsing Department of Medical Imaging and Clinical Oncology by Subject "Androgen deprivation therapy"

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    Radiosensitisation of androgen-dependent and independent tumour cells as a therapeutic strategy in prostate cancer
    (Stellenbosch : Stellenbosch University, 2019-12) Maleka, Sechaba; Akudugu, J. M.; Serafin, A. M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medical Imaging and Clinical Oncology. Radiobiology.
    ENGLISH SUMMARY : Metastatic prostate cancer continues to be a leading cause of cancer-related death in men. Increased incidences and mortality have been reported globally, although treatment of locally confined prostate cancer has been shown to be successful. However, aggressive and incurable castration-resistant prostate cancer (CRPC) is a major clinical concern. The combination of radiotherapy and androgen deprivation therapy (ADT) is the current standard-of-care treatment strategy for prostate cancer (PCa). The androgendependent stage of tumour is successfully managed, until the cancer switches to androgen-independence when resistance to treatment severe. The mechanism underlying this switch is still not clear and poorly understood. However, the implicated survival pathways of PI3K/mTOR, EGFR and AR might help explain remissions of PCa after treatment. Thus, the rationale for this study was to target these pathways with respective inhibitors, namely, MDV3100 (for AR), AG-1478 (for EGFR), and NVPBEZ235 (for PI3K and mTOR). The “traditional” prostate cancer cell lines, (DU145 and LNCaP), which are derived from metastatic regions, and (1542N and BPH-1) from normal tissue and a primary benign tumour, respectively, served as biological models in this research. The following were investigated: (1) androgen sensitivity of cell lines, (2) the intrinsic cellular radiosensitivity, (3) the cytotoxicity of specific inhibitors of AR, EGFR, PI3K and mTOR, (4) interaction of the respective inhibitors, and (5) the radiomodulatory effects of inhibitors, either singly or in combination. The “classical” androgen-independent cell lines were found to switch into androgendependence when treated with high concentrations of 5α-DHT. Very strong synergistic interactions of inhibitors were demonstrated in all cell lines, except the LNCaP cell line in which inhibitors were antagonistic. Concomitant use of these inhibitors in intrinsically androgen-dependent prostate cancers might not be beneficial. The use of inhibitor cocktails with radiation at low doses (2 Gy) is highly desirable as the normal cells were protected, especially with the dual inhibitor of PI3K/mTOR (NVP-BEZ235). However, at higher doses (6 Gy) the potential benefit is great in tumour cell lines, but very limited in the normal cell line. Therefore, at fractional doses of relevance to conventional radiotherapy, use of cocktails containing the PI3K/mTOR inhibitor as an adjuvant may be beneficial in the management of androgen-dependent cancer. It is concluded that these findings might assist in the design of more effective treatment approaches for cancers that typically display resistance to radiotherapy and chemotherapy.