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Contains fulltext : 177889.pdf (Publisher’s version ) (Open Access) The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

The therapeutic concept of administering agents (cytotoxic/-static,non-cytotoxic and/or targeted drugs) continuously at lower doses - relative to MTDs in the case of cytostatic and cytotoxic drugs or continuously at tolerable doses as in the case of targeted drugs without drug-free breaks over extended periods - known as ‘metronomic therapy’ (MT), is increasingly being recognized as an experimental option for treating cancer. In comparison with MTD-defined chemotherapy (CHT) regimens, metronomic therapy has demonstrated reduced toxicity. More importantly, several phase II trials have shown that metronomic therapies showed anti-cancer activity in different cancer types with different drugs. The mechanistic basis of metronomic therapy using cytotoxic/static drugs is believed to be primarily anti-angiogenic, either by direct killing or inhibiting endothelial cells (ECs) in the tumor vasculature, killing bone-marrow-derived endothelial progenitor cells, stimulating the immune system, directly affecting tumor cells through a drug-driven effect as well as specificly inhibiting a target when targeting drugs were used in additional to metronomic therapy. The induction of senescence in cancer is another possible explanation for the principles behind ‘metronomic therapy’.

The electrophoresis-mobility test is an in-vitro method for demonstrating specific sensitized lymphocytes. After incubation with the encephalitogenic factor, lymphocytes from patients with malignant disease liberate a factor which causes a decrease in migration velocity of indicator cells (tanned and sulphosalicyl acid-stabilised sheep erythrocytes = ETS) in an electrical field. 84 patients with pulmonary disease and 20 control persons were examined. An inhibition of ETS migration was found only in patients with malignant pulmonary disease, while in the control subjects and those with inflammatory or degenerative pulmonary disease or benign pulmonary tumour ETS migration was accelerated. The difference between the two groups is statistically significant so that it provides a reliable differentiation between benign and malignant disease. False-negative results, however, occur under radiotherapy and chemotherapy.

alpha- and gamma-enolase isoenzyme substance concentrations were measured in serum and plasma from healthy subjects and from 174 patients with different solid tumours. While alpha-enolase was found to be increased in the plasma of patients with tumours of quite different origin, gamma-enolase apparently reflected malignancies of the neuroendocrine system. Before the beginning of the cytotoxic therapy gamma-enolase was increased above the upper limit of the reference range (10 micrograms/l) in 27/27 patients (100%) suffering from small cell lung cancer. Most patients with squamous cell carcinoma of the lung or with prostatic cancer exhibited normal gamma-enolase, while both tumour types produced high plasma substance concentrations of the alpha-isoenzymes of enolase.