~ Reports From Canada, The United States And Germany Describe Recent Advances In Prostate Cancer Research

NewsRx.com, 07-07-06

Data on prostate cancer are outlined in reports from Canada, the United States and Germany.

Study 1: Prostate cancer angiogenesis submits to the synthetic peptide PCK3145.

According to a study from Canada, "We have previously observed that the synthetic peptide corresponding to amino acids 31-45 (PCK3145) of PSP94 can reduce prostate tumor growth in vivo. Moreover, a recently concluded phase IIa clinical trial with patients with hormone refractory prostate cancer indicated that PCK3145 down-regulates the levels of plasma matrix metalloproteinase (MMP)-9, a MMP involved in metastasis and tumor angiogenesis."

"The purpose of our study was to investigate the molecular mechanisms of action of PCK3145 and whether this peptide could antagonize tumor neovascularization. We show that, in a syngeneic in vivo model of rat prostate cancer, the expression of endothelial cell (EC) specific CD31, a marker of tumor vessel density, was decreased by 43% in PCK3145-treated animals," wrote S. Lamy and colleagues, University of Quebec.

Scientists said, "In vitro, PCK3145 specifically antagonized in a dose-dependent manner the VEGF (vascular endothelial growth factor)-induced ERK phosphorylation as well as the phosphorylation of the VEGFR-2 in culture EC (HUVEC). These anti-VEGF effects were partly reproduced by pharmacological inhibitors such as PD98059 and PTK787, suggesting that PCK3145 inhibits the tyrosine kinase activity associated to VEGFR-2, which in turn prevents intracellular signaling through the MAPK cascade.

"Moreover, PCK3145 was also found to inhibit the PDGF-induced phosphorylation of PDGFR in smooth muscle cells. Finally, PCK3145 inhibited in vitro EC tubulogenesis and VEGF-induced MMP-2 secretion suggesting its potential implication as an antiangiogenic agent. Our study demonstrates that PCK3145 interferes with the tyrosine kinase activity associated with VEGF signaling axis in EC."

"The antiangiogenic properties of this peptide could be highly beneficial and exploited in novel antiangiogenic therapies, for patients with various cancers," scientists concluded.

Lamy and colleagues published their study in International Journal of Cancer (A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: Implication in tumor angiogenesis. Int J Cancer, 2006;118(9):2350-2358).

For more information, contact B. Annabi, University of Quebec, Oncology Molecular Laboratory, Dept. Chim Biochim, CP 8888, Succ Center Ville, Montreal, PQ H3C 3P8, Canada.

Study 2: Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) were evaluated as potential therapeutic modalities for prostate cancer.

"This review focuses on the promising roles of PSP-94 and PCK3145 as potential therapeutic modalities for prostate cancer and its associated complications. Evaluation of these compounds was carried out in vitro and in vivo using syngeneic models of rat prostate cancer," scientists writing in the journal Anti-Cancer Drugs reported.

"Overproduction of parathyroid hormone-related protein (PTHrP) results in the development of hypercalcemia of malignancy in several malignancies including prostate cancer," explained N. Shukeir and colleagues, McGill University.

"In order to evaluate the effect of PSP-94 and PCK3145 on prostate cancer progression, the rat Dunning 83227 MatLyLu cell line transfected with full-length cDNA encoding PTHrP (MatLyLu-PTHrP) was used. As the main pathogenetic factor of hypercalcemia of malignancy, overexpression of PTHrP was aimed at mimicking the hypercalcemic nature seen in patients suffering from late-stage cancer."

"In vitro studies showed that PSP-94 and PCK3145 can cause a dose-dependent inhibition in the growth of MatLyLu-PTHrP cells. For in vivo studies, male Copenhagen rats were inoculated either s.c. into the right flank or directly into the left ventricle via intracardiac (i.c.) inoculation with MatLyLu-PTHrP cells. In these models, s.c. injection of MatLyLu cells results in the development of primary tumor growth, whereas i.c. inoculation routinely results in the development of experimental skeletal metastases in the lumbar vertebrae causing hind-limb paralysis."

The investigators observed, "Administration of PSP-94 and PCK3145 into tumor-bearing animals resulted in a dose-dependent inhibition of primary tumor growth, and tumoral and plasma PTHrP levels, and in the reduction of plasma calcium levels. Additionally, treatment with PSP-94 or PCK3145 caused an inhibition of skeletal metastases resulting in a significant delay in the development of hind-limb paralysis."

"Interestingly, equimolar concentrations of PCK3145 were shown to be more effective in delaying the development of experimental skeletal metastases as compared to PSP-94. One of the possible mechanisms of action of these modalities is through the induction of apoptosis, which was observed by both in-vitro and in-vivo analyses of MatLyLu-PTHrP cells and tumors. Several intracellular mechanisms can also be involved in inhibiting PTHrP production and anti-tumor effects of PSP-94 and PCK3145."

The researchers concluded, "Collectively, these studies warrant the continued clinical development of these agents as therapeutic agents for patients with hormone-refractory prostate cancer."

Shukeir and colleagues published their study in Anti-Cancer Drugs (Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) as potential therapeutic modalities for prostate cancer. Anticancer Drugs, 2005;16(10):1045-1051).

Additional information can be obtained by contacting S.A. Rabbani, McGill University, Center Health, Dept. Med Physiol & Oncology, 687 Pine Avenue W, Room H4-68, Montreal, PQ H3A 1A1, Canada.

The publisher of the journal Anti-Cancer Drugs can be contacted at: Lippincott Williams & Wilkins, 530 Walnut St., Philadelphia, PA 19106-3261, USA.

Study 3: Modular dipeptide mimetics were synthesized.

"We present the synthesis of new modular dipeptide mimetics based on diazabicycloalkane backbones. These diazabicycloalkanes are ligands for the prostate specific membrane antigen (PSMA), a well known tumor marker," scientists writing in the journal Amino Acids reported.

"Our previously described synthetic route to enantiomerically pure diazabicycloalkanes is extended to yield polyfunctional diazabicycloalkanes with a modular character using a new ring closing methodology. This, finally, allows us to attach linker moieties to different positions of the diazabicycloalkane scaffold providing conjugation sites to other functional molecules such as markers or cytostatic compounds," explained D.C. Grohs and colleagues, University of Hamburg.

The researchers concluded, "Furthermore, successful synthesis of sulphur-containing dipeptide analogues as for example CysX(AA)- or HCysX(AA)-mimetics on the basis of diazabicycloalkanes is described."

Grohs and colleagues published their study in Amino Acids (Synthesis of modular dipeptide mimetics on the basis of diazabicycloalkanes and derivatives thereof with sulphur containing side chains. Amino Acids, 2005;29(2):131-138).

Additional information can be obtained by contacting W. Maison, University of Hamburg, Institute Organ Chemical, Hamburg, Germany.

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