Tumor biology and cancer therapy - an evolving relationship.

The aim of palliative chemotherapy is to increase survival whilst maintaining maximum quality of life for the individual concerned. Although we are still continuing to explore the optimum use of traditional chemotherapy agents, the introduction of targeted therapies has significantly broadened the therapeutic options. Interestingly, the results from current trials put the underlying biological concept often into a new, less favorable perspective. Recent data suggested that altered pathways underlie cancer, and not just altered genes. Thus, an effective therapeutic agent will sometimes have to target downstream parts of a signaling pathway or physiological effects rather than individual genes. In addition, over the past few years increasing evidence has suggested that solid tumors represent a very heterogeneous group of cells with different susceptibility to cancer therapy. Thus, since therapeutic concepts and pathophysiological understanding are continuously evolving a combination of current concepts in tumor therapy and tumor biology is needed. This review aims to present current problems of cancer therapy by highlighting exemplary results from recent clinical trials with colorectal and pancreatic cancer patients and to discuss the current understanding of the underlying reasons.

Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells.

Chromogranin A is a member of the granin family of acidic secretory glycoproteins that is found in secretory granules of many endocrine cells including neuroendocrine tumour cells. This hormone serves as a model system for autonomous hormone secretion by the so called functional neuroendocrine tumours of the gastrointestinal tract. The precise regulation of chromogranin secretion at the level of the Golgi apparatus is a subject of intense research. The protein kinase D (PKD) family of serine threonine kinases has so far been implicated in the regulation of constitutive secretion in epithelial cells. Here we examined whether PKD2 expression and activity could also play a role in the release of secretory granules from the trans Golgi network (TGN) in neuroendocrine tumour cells and hence be a target to block autonomous secretion by these tumours. Our data show that expression and catalytic activity of PKD2 are required for the release of chromogranin A containing secretory vesicles. Inhibition of PKD2 activity or siRNA knockdown of PKD2 resulted in a marked perinuclear retention of chromogranin A immunofluorescence in the trans Golgi network and led to a marked reduction in basal as well as phorbol ester stimulated secretion of chromogranin A into the supernatant of cells. Thus, PKD2 controls the release of secretory granules in neuroendocrine tumour cells at the level of the Golgi apparatus and could hence serve as a novel target to block hormone secretion in functional neuroendocrine tumours.

Influence of neonatal sympathectomy on proximal renal resistance artery function in spontaneously hypertensive rats.

Renal transplantation experiments have shown that the kidney contributes to chronic sympathectomy-induced arterial pressure reduction in spontaneously hypertensive rats (SHR). The underlying mechanisms are currently unclear but may include alterations in the function of small renal arteries. Neonatal SHR were sympathectomized by intraperitoneal guanethidine injections and removal of adrenal medullary tissue. Controls were sham- or hydralazine-treated. At 12 weeks of age, distal interlobar artery segments were investigated using small-vessel wire myography. Vessels from sympathectomized animals showed increased sensitivity to noradrenaline (NE). Vasopressin- and endothelin-1-induced vasoconstriction was similar in all groups (as reflected by the pD(2), i.e. -logEC(50), where EC(50) is the molar concentration of agonist eliciting a half-maximal response). Maximum vasopressin-induced tension was similar in all groups while endothelin-1-induced maximum tension was significantly higher in sympathectomized than in sham-treated SHR. The sensitivity of NE-induced vasoconstriction to extracellular Ca(2+) did not differ between groups while sensitivity to L-type Ca(2+) channel activation was significantly higher in both sympathectomized and hydralazine-treated animals than in sham-treated animals. Endothelium-dependent and independent vasodilation were similar in all groups. Sequential blockade of NO-synthase and cyclooxygenase had similar effects in all groups. In conclusion, neonatal sympathectomy does not induce any changes in the function of isolated proximal renal resistance arteries from SHR that could explain the blood pressure lowering effect of a kidney graft from sympathectomized SHR.