Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

The somatostatin analogue SOM230, compared with octreotide, induces differential effects in several metabolic pathways in acromegalic patients

OBJECTIVE: Recently, our first clinical study with the novel multiligand somatostatin (SRIF) analogue SOM230 in acromegalic patients showed that SOM230, due to its beneficial inhibitory effects on GH levels compared with octreotide (OCT), might increase the number of patients that can be biochemically controlled. Since SRIF analogues are also known to interact with other metabolic pathways, IGF-I, IGFBP-1, glucose and insulin concentrations on the control day (CD) and on treatment days following a single s.c. injection SOM230 100 and 250 microg, were compared to those following OCT 100 microg. DESIGN AND PATIENTS: Randomized, cross-over, double-blinded proof-of-concept trial in 12 patients with active acromegaly. RESULTS: Free IGF-I levels were suppressed after 24 h by OCT, SOM230 250 and 100 microg, whereas at 48 h only both SOM230 dosages still induced these inhibitory effects. Circulating IGFBP-1 levels (AUC; 0830-1430 h) compared with CD, increased sharply after OCT (from 48 to 237 microg/l/h; P < 0.001 vs. CD), while SOM230 250 and 100 microg elicited a lower and dose-dependent effect (163 and 90 microg/l/h, respectively, P < 0.05 vs. CD and OCT). Neither insulin nor GH levels showed statistically significant correlation with IGFBP-1 levels either after SOM230 or OCT. An early rise in glucose levels 1 h postinjection with SOM230 250 microg compared with OCT and CD was observed 8.3 +/- 0.8, 4.4 +/- 0.5 and 4.9 +/- 0.4 mmol/l, respectively: P < 0.05). SOM230 250 microg (19 +/- 4 vs. 46 +/- 3 mU/l on CD: P < 0.05), although clearly less potent than OCT (5.4 +/- 0.4 mU/l: P < 0.01 vs. CD), inhibited insulin release. Since these corresponding absolute insulin levels cannot entirely explain this hyperglycaemic effect of SOM230, other mechanisms seem involved in this glucose rise. If SOM230 would influence glucose homeostasis in peripheral target tissues of insulin action, expression of SS-receptors (sst) seems a logical necessity. In normal human liver tissues, analysed by quantitative polymerase chain reaction (PCR), the average sst1 mRNA expression level appeared significantly higher compared with sst2 (n = 6, relative copy number 161 +/- 46 vs. 57 +/- 6; P < 0.05). Fat tissue expressed both sst1 and sst2 mRNA, whereas in muscle only sst2 mRNA was found. CONCLUSION: Both dosages of SOM230 inhibit free IGF-I in a more sustained fashion compared to OCT, implying longer duration of action. The superior action of OCT compared with SOM230 in stimulating IGFBP-1 levels, suggests direct regulation of IGFBP-1 by SRIF analogues via sst2. Finally, expression of only sst1 and sst2 in target tissues of insulin action, might point towards additional modulatory effects by SOM230 on glucose homeostasis.     

Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors.

PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy. EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX). RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks. CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.     

Effects of simultaneous aortocaval occlusion on oxygen consumption in patients

The effects of simultaneous occlusion of the thoracic aorta and inferior vena cava on oxygen consumption (V O 2) have not yet been reported in humans. Ten patients (all ASA II) needed such simultaneous occlusion to allow hypoxic abdominal perfusion in the treatment of pancreatic cancer. With the development of the PhysioFlex anaesthesia machine for closed-circuit anaesthesia, intra-operative real-time curves of V O 2 became available. Thus, we can continuously measure F I O 2, V E, V O 2, and air consumption. By placing a pulmonary artery catheter, we could also intermittently calculate D O 2 during the several phases of the perfusion procedure. Immediately after the simultaneous aortocaval occlusion started, V O 2 decreased by 35% (68 ml min-1 m-2) and D O 2 decreased below the critical value of 330 ml min-1 m-2. At reperfusion, repayment of the oxygen debt was by a two-stage pattern: a fast repayment stage with an increase of about 65% was followed by a slow repayment stage of 14% increase (values compared to steady state). Oxygen consumption in women was found to be significantly lower than in men (P = 0.02), with significant variation between the sexes during different stages of the procedure. The oxygen debt was not completely repaid by the end of the procedure. We conclude that the significant variation found in oxygen consumption will have consequences while performing low-flow anaesthesia, that additional oxygen supply during the recovery period because of the initially incomplete repayment of oxygen debt may be useful and that studies on oxygen consumption must present gender-specific data because of the gender-dependent variation found in oxygen consumption.     

The pathophysiological consequences of somatostatin receptor internalization and resistance

Somatostatin receptors expressed on tumor cells form the rationale for somatostatin analog treatment of patients with somatostatin receptor-positive neuroendocrine tumors. Nevertheless, although somatostatin analogs effectively control hormonal hypersecretion by GH-secreting pituitary adenomas, islet cell tumors, and carcinoid tumors, significant differences are observed among patients with respect to the efficacy of treatment. This may be related to a differential expression of somatostatin receptor subtypes among tumors. In addition, the property of somatostatin receptor subtypes to undergo agonist-induced internalization has important consequences for visualizing, as well as for therapy, of receptor-positive tumors using radioisotope- or chemotherapeutic-compound-coupled somatostatin analogs. This review covers the pathophysiological role of somatostatin receptor subtypes in determining the efficacy of treatment of patients with somatostatin receptor-positive tumors using somatostatin analogs, as well as the preclinical and clinical consequences of agonist-induced receptor internalization for somatostatin receptor-targeted radio- and chemotherapy. Herein, the development and potential role of novel somatostatin analogs is discussed.