Adriamycin in combination with dexamethasone and octreotide lacks activity on the treatment of a 4T1 metastatic breast cancer model.

The aim of this study was to evaluate whether the palliative treatment for metastatic disease with dexamethasone (DEX) plus octreotide (OCT) can improve the anticancer effects of the standard treatment with adriamycin (ADR) on a 4T1 metastatic breast cancer (MBC) model. 4T1 cells were first characterized for the expression of the somatostatin receptors 1-5 and were then inoculated onto the femur of BALB/C mice. Investigation protocols used 4T1 cell proliferation and invasion assays, analysis of radiographic images of the bone metastatic lesions, and overall survival of the diseased animals. The triple combination treatment regime (ADR+OCT+DEX) was ineffective for growth inhibition and showed an antagonistic effect on ADR activity in the 4T1 cell line in both proliferation and invasion assays. ADR treatment following the administration of the DEX+OCT regimen decreased the anticancer activity of ADR both on the grading of the bone metastatic lesions and on the overall survival of diseased animals. Moreover, the palliation treatment with OCT+DEX and in combination with ADR rather caused disease progression of the metastatic disease and bone lesions in a 4T1 MBC model in vivo. These results suggest that the administration of the DEX+OCT regimen, although may preserve palliative effects, neutralizes or reverses the anticancer effects of ADR on a 4T1 MBC model in vitro and in vivo. The simultaneous use of these drugs should be considered carefully in clinical practice.

IGF1Ec expression in MG-63 human osteoblast-like osteosarcoma cells.

AIM: The insulin-like growth factor 1 (IGF1) gene gives rise to multiple transcripts, using an elaborate alternative splicing mechanism. The aim of this study was to shed light on the expression and role of the IGF1 system in human MG-63 osteoblast-like osteosarcoma cells. MATERIALS AND METHODS: The expression of the IGF1Ea, IGF1Eb and IGF1Ec isoforms was characterized using reverse transcription polymerase chain reaction (RT-PCR), quantitative real time-PCR (qRT-PCR) and western blot analysis. Using trypan blue exclusion assays, we also examined the mitogenic effects of IGF1 and of a synthetic peptide related to the E domain of IGF1Ec (synthetic E peptide) on MG-63 cells, as well as on MG-63 cells which had been molecularly modified to restrain the expression of type I IGF receptor (IGF1R) and of insulin receptor (INSR) by siRNA techniques (IGF1R KO or INSR KO MG-63 cells). RESULTS: MG-63 cells express only the IGF1Ea and IGF1Ec transcripts. Exogenous administration of dihydrotestosterone (DHT) significantly increased the expression of IGF1Ea and IGF1Ec mRNA and it induced the previously undetectable expression of IGF1Eb transcript. Exogenous administration of IGF1, insulin and the synthetic E peptide stimulated the growth of MG-63 cells, while only E peptide stimulated the growth of IGF1R KO and INSR KO MG-63 cells. CONCLUSION: These data suggest that the expression of all IGF1 isoforms is hormonally regulated in MG-63 cells and that the expression of IGF1Ec may be involved in osteosarcoma biology by generating the Ec peptide which acts via an IGF1R-independent and INSR-independent mechanism.

Mechanisms of bone metastasis in prostate cancer: clinical implications.

Prostate cancer shows a strong predilection to spread to the bones. Once prostate tumour cells are engrafted in the skeleton, curative therapy is no longer possible and palliative treatment becomes the only option. Herein, we review the multifactorial mechanisms and complex cellular interactions that take place inside the bone metastatic microenvironment. Emphasis is given to the detection and treatment of the micrometastatic stage of prostate cancer, as well as our recent attempts to target the bone metastasis microenvironment-related survival factors using an anti-survival factor manipulation which can increase the efficacy of anticancer therapies such as androgen ablation therapy and chemotherapy in advanced prostate cancer.

Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: a bench to bedside approach.

The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.

The glutamatergic system outside the CNS and in cancer biology.

Glutamate is a major excitatory neurotransmitter in the CNS. The signalling machinery consists of: glutamate receptors, which are responsible for signal input; plasma glutamate transporters, which are responsible for signal termination; and vesicular glutamate transporters for signal output through exocytic release. Recently, data have suggested that the glutamatergic system plays an important role in non-neuronal tissues. In addition, the expression of glutamatergic system has been implicated in tumour biology. This review outlines the evidence, which suggests that the glutamatergic system may have an important role in cancer biology.