Implications For Prostate Cancer Treatment And Prevention

Elevated levels of circulating IGF-1, which are strongly associated with the risk of developing prostate cancer, are measured long before presentation of this cancer. IGF may be a new tool for prostate cancer risk assessment and reduction. Recent research projects indicated that current androgen-targeting therapies alter IGF physiology within androgen-responsive cells in a manner that contributes to apoptosis associated with androgen withdrawal. Several IGF binding proteins undergo an impressive up-regulation following castration but preceding the onset of castration-induced apoptosis.57 Similar results were observed for antiandrogens58 and growth inhibitory vitamin D analogs.58'59 Recent data support the view that, in androgen-dependent tissues, IGFBP expression is suppressed by androgens and that, at the time of androgen withdrawal, IGFBP expression rises, leading to a massive decline in IGF bioactivity, thereby promoting apoptotic cell death, given the known antiapoptotic IGF activity.

Currently, the hypothesis that the efficacy of androgen-targeting therapies can be improved by combining them with IGF targeting therapies is under investigation. Other possible IGF-related approaches include the use of suppressors of IGF-1 expression (including GHRH antagonists and somatostatin analogs), IGF receptor blocking or antisense strategies, growth hormone antagonists and the use of IGF binding protein protease inhibitors. Inducers of expression of IGF binding proteins, including vitamin D-related compounds and the enhancement of cytotoxic chemotherapy by coadmin-istration of agents that reduce IGF bioactivity, given the known antiapoptotic properties of IGF, are also under active investigation. This line of research has been stimulated by the results of preclinical studies and subsequent clinical trials that demonstrate enhanced efficacy of cytotoxic drugs in the presence of blockers of the HER2 receptor.58-60 Small molecule inducers of IGF binding protein expression and of inhibitors of IGFBP proteolysis might have activity even for tumors with IGF autocrine loops, as would approaches that have the IGF receptor itself as a target. GHRH antagonists show surprisingly strong activity in models of aggressive prostate cancer, raising the possibility of novel mechanisms of action mediated by GHRH receptors on neoplastic cells, including the inhibition of IGF-2 expression.61 P,P-Dimethyl acryl shikonin, an extract from the root of plant Arnebia nobilis has been shown to have anticancer properties but was found to be toxic. Several analogs of P,P-dimethyl acryloyl shikonin were synthesized and one of them, shikonin analog 93/637 (SA), was significantly less toxic. SA exerts an inhibitory effect on cellular growth and IGFs (up-regulating IGFBP-3, down-regulating local IGF-1 and IGF-1R), specifically in PC-3 cells.62 The inhibitory effects of GHRH antagonists on PC-3 androgen-independent prostate cancer can be potentiated by concomitant use of bombesin/gastrin-releasing peptide antagonists. The combination of both types of analog apparently interferes with the IGF (a decrease in IGF-1) and bombesin/ EGF pathways.63

The recent epidemiological observations that link IGF-1 to prostate cancer risk may have implications for future prevention strategies.64,65 IGF represents a individual host characteristic that appears to be related to the probability of future carcino-genesis. Relative to other hormones, IGF-1 levels fluctuate little over time.

Men with high IGF-1 levels might benefit from enhanced screening procedures, including PSA screening. It has been proposed that a single IGF-1 measurement might be used to define a subset of the population for whom annual PSA screening for prostate cancer detection might be advisable at an early age. It might be premature to suggest intervention studies that would evaluate potential benefits of pharmacological reduction of IGF-1 levels from high-normal to mid-normal values. Long-term safety data are available for somatostatin analogs, which are one of several candidate molecules that reduce IGF-1 levels. Octreotide, a somatostatin analog, decreases the hepatic production of IGF-1 and glucocorti-coids, such as dexamethasone, have been demonstrated to decrease the tissue levels of IGF-1 in bone.66,67 However, their potential to lower levels from the 'high-normal' to 'mid-normal' range is still under investigation. It is possible that dose-response relationships might be influenced by pretreatment IGF-1 level. There is no rationale for proposing to lower levels to below the normal range for the purpose of prevention. The goal would be to move IGF serum level in men from 'highnormal' to 'low-normal'. Right now current monthly depot formulations are not the optimum for long-term use. However, the development of orally active IGF-1 suppressing drugs should be possible in the near future.

Potential IGF-1 targeting prevention strategies would be suitable only for the proportion of the population (10-20%) at increased risk specifically associated with high IGF-1 level or low IGFBP-3 level. A strategy aimed at a rise in IGFBP-3 level could also lower risk. Practical lifestyle modifications that could be used to lower levels have not been described to date.

In the past few years, the axis of ligands, receptors and binding proteins that forms the IGF system has received substantial attention. Considerable evidence has accumulated that links this complex system to the pathophysiology of prostate cancer. The accumulated data suggest novel treatment and prevention strategies for this very common cancer. Future research may concentrate on the manipulation of IGF in the management of prostate cancer or in its chemoprevention either by therapeutic regulation of IGF-1 levels in the upper quartile or by dietary modification.

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