Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients.

Pleiotrophin is a heparin-binding growth factor involved in the differentiation and proliferation of neuronal tissue during embryogenesis, and also secreted by melanoma and breast carcinoma cells. Pleiotrophin exhibits mitogenic and angiogenic properties and has been shown to influence the vascular supply, expansion and metastasis of tumour cells. Our aim was to study the serum and plasma concentrations of pleiotrophin and the classical angiogenic growth factor vascular endothelial growth factor. Using a specific ELISA-test we studied patients with small cell lung cancer (n=63), and patients with non-small cell lung cancer (n=22) in comparison to healthy control subjects (n=41). In most of the lung cancer patients (81%), we found serum levels of pleiotrophin above those of control subjects (P<0.001). Of the 63 small cell lung cancer patients in the study pleiotrophin serum levels were elevated in 55 cases (87%) and in 14 cases (63%) of the 22 non-small cell lung cancer patients. Pleiotrophin mean serum concentrations were 10.8-fold higher in the tumour patient group as compared to the control group (P<0.001). Furthermore, pleiotrophin serum levels correlated positively with the stage of disease and inversely with the response to therapy. Plasma vascular endothelial growth factor concentrations were elevated in only in 28.6% of small cell lung cancer and 45.5% of non-small cell lung cancer patients by an average of 2.3-fold. Quite strikingly, there was no apparent correlation between the plasma vascular endothelial growth factor concentration and the stage of disease. Our study suggests that pleiotrophin may be an early indicator of lung cancer and might be of use in monitoring the efficacy of therapy, which needs to be confirmed by larger studies.

Catalytic antibodies as magic bullets.

A reagent capable of detecting and selectively destroying tumor cells while leaving healthy cells intact would be a powerful tool for cancer therapy. This concept of the magic bullet has been approached by a number of strategies. Here we present a recent approach based on catalytic antibodies.

Multiple event activation of a generic prodrug trigger by antibody catalysis.

Chemotherapeutic regimes are typically limited by nonspecific toxicity. To address this problem we have developed a broadly applicable drug-masking chemistry that operates in conjunction with a unique broad-scope catalytic antibody. This masking chemistry is applicable to a wide range of drugs because it is compatible with virtually any heteroatom. We demonstrate that generic drug-masking groups may be selectively removed by sequential retro-aldol-retro-Michael reactions catalyzed by antibody 38C2. This reaction cascade is not catalyzed by any known natural enzyme. Application of this masking chemistry to the anticancer drugs doxorubicin and camptothecin produced prodrugs with substantially reduced toxicity. These prodrugs are selectively unmasked by the catalytic antibody when it is applied at therapeutically relevant concentrations. We have demonstrated the efficacy of this approach by using human colon and prostate cancer cell lines. The antibody demonstrated a long in vivo half-life after administration to mice. Based on these findings, we believe that the system described here has the potential to become a key tool in selective chemotherapeutic strategies.

Characterization of neuronal amino acid transporters: uptake of nitric oxide synthase inhibitors and implication for their biological effects.

In the present study we investigated uptake of the nitric oxide (NO) synthase inhibitors NG-methyl-L-arginine and NG-nitro-L-arginine by the mouse neuroblastoma x rat glioma hybrid cell line NG108-15. Uptake of NG-methyl-L-arginine was characterized by biphasic kinetics (Km1 = 8 mumol/L, Vmax1 = 0.09 nmol x mg-1 x min-1; Km2 = 229 mumol/L, Vmax2 = 2.9 nmol x mg-1 x min-1) and was inhibited by basic but not by neutral amino acids. Uptake of NG-nitro-L-arginine followed Michaelis-Menten kinetics (Km = 265 mumol/L, Vmax = 12.8 +/- 0.86 nmol x mg-1 x min-1) and was selectively inhibited by aromatic and branched chain amino acids. Further characterization of the transport systems revealed that uptake of NG-methyl-L-arginine is mediated by system y+, whereas systems L and T account for the transport of NG-nitro-L-arginine. In agreement with these data on uptake of the inhibitors, L-lysine and L-ornithine antagonized the inhibitory effects of NG-methyl-L-arginine on bradykinin-induced intracellular cyclic GMP accumulation, whereas L-tryptophan, L-phenylalanine, and L-leucine interfered with the effects of NG-nitro-L-arginine. These data suggest that rates of uptake are limiting for the biological effects of NO synthase inhibitors.

Experimental hypothalamic dysfunction in dogs.

The authors demonstrate an experimental model in dogs developed in order to study endocrine disorders as a result of suprasellar space occupying lesion. Fogarty balloon catheters were inserted in dogs below the optic chiasm and filled with contrast medium. The study of thyroid function shows that initially reversible hypothalamic hypothyroidism develops and that in a second stage most animals develop chronic thyroid dysfunction which is irreversible even after careful removal of the experimental tumor. The clinical symptoms correlate with these findings. Morphological examinations prove the fact that the hypothalamic disorders are due to disturbances of the blood-brain-barrier in the hypothalamus following hypothalamic compression and decompression.