Abstract
Ionizing radiation (IR) is the most common treatment used to control localized primary prostate cancer (PC). However, for a significant number of patients, radiotherapy fails to adequately control the tumor. Thus, a main clinical problem today is the lack of a specific marker that may be used to predict the treatment outcome and to identify prostate cancer patients who are unlikely to respond to radiation therapy. In this study, we used human PC xenografts with predetermined radioresistant/sensitive phenotypes, and gene expression microarrays, correlated their specific transcripttional profiles with response to radiation. Employing unsupervised two-way hierarchical clustering, we identified four gene clusters displaying different expression patterns. Two clusters showed higher expression levels in the resistant xenografts and the other two clusters showed higher expression levels in the sensitive xenografts. Expression levels of 113 genes differed by at least 3 fold between sensitive and resistant xenografts. These genes represent members of several cellular pathways, some of which are known to be associated with response to radiation. All or several of these genes could serve as predictive tools to determine at biopsy the expected response of a particular tumor to radiotherapy. Indeed, the profiles we identified enabled us to predict the degree of radiosensitivity of a panel of established PC cell lines. Importantly, irradiation of the PC xenografts did not induce any significant changes in gene expression, regardless of their susceptibility phenotype. These data strongly support the first of two models: a: a random effect of irradiation on a homogeneous population of cells, rather than b: of a tumor comprised of a mixture of radioresistant and radiosensitive cell subpopulations. Our findings imply that each of the radio-phenotypes represents different intrinsic characteristics that affect the ability of a tumor to survive radiotherapy.
Highlights
Surgery and radiotherapy are the mainstays of treatments for localized primary prostate cancer (PC)
To determine the gene expression profile of the various human prostate cancer adenocarcinoma xenografts and cell lines, we first evaluated their ability to grow under the skin of SCID mice following either a single in vitro irradiation dose or fractionated irradiation in SCID mice
The Ionizing radiation (IR) resistant phenotype is exemplified by LAPC9 (Figure 1(b)), which formed tumors even following to a dose of 160 Gy
Summary
Surgery and radiotherapy are the mainstays of treatments for localized primary prostate cancer (PC). Direct comparisons between patients treated with ionizing radiation (IR) and prostatectomy are lacking, and there is no consensus regarding the relative effectiveness of these two therapies [1]. The lack of a predictive measure to determine the outcome of radiotherapy results in administration of excessive irradiation to a large proportion of patients, or ineffective treatment of patients with radioresistant tumors. External radiation therapy is given over a 7 to 8 week period with a total of 65 78 Gray (Gy) delivered in 1.8 - 2 Gy fractions to the prostate. Patients can receive low doses (/=72 Gy) of external-beam radiotherapy depending on disease severity [1]. Results from randomized clinical trials showed a 45% reduction in disease recurrence among patients assigned to high dose (78 Gy)
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