Novel Phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416.

PURPOSE: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose. EXPERIMENTAL DESIGN: Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. RESULTS: Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of >35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. CONCLUSION: SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.

Synthesis and evaluation of a polydisulfide with Gd-DOTA monoamide side chains as a biodegradable macromolecular contrast agent for MR blood pool imaging.

Macromolecular Gd(III)-based contrast agents are effective for contrast-enhanced blood pool and cancer MRI in preclinical studies. However, their clinical applications are impeded by potential safety concerns associated with slow excretion and prolonged retention of these agents in the body. To minimize the safety concerns of macromolecular Gd contrast agents, we have developed biodegradable macromolecular Gd contrast agents based on polydisulfide Gd(III) complexes. In this study, we designed and synthesized a new generation of the polydisulfide Gd(III) complexes containing a macrocyclic Gd(III) chelate, Gd-DOTA monoamide, to improve the in vivo kinetic inertness of the Gd(III) chelates. (N6-Lysyl)lysine-(Gd-DOTA) monoamide and 3-(2-carboxyethyldisulfanyl)propanoic acid copolymers (GODC) were synthesized by copolymerization of (N6-lysyl)lysine DOTA monoamide and dithiobis(succinimidylpropionate), followed by complexation with Gd(OAc)3. The GODC had an apparent molecular weight of 26.4 kDa and T1 relaxivity of 8.25 mM(-1) s(-1) per Gd at 1.5 T. The polymer chains of GODC were readily cleaved by L-cysteine and the chelates had high kinetic stability against transmetallation in the presence of an endogenous metal ion Zn(2+). In vivo MRI study showed that GODC produced strong and prolonged contrast enhancement in the vasculature and tumor periphery of mice with breast tumor xenografts. GODC is a promising biodegradable macromolecular MRI contrast agent with high kinetic stability for MR blood pool imaging.

5HTTLPR predicts left fusiform gyrus activation to positive emotional stimuli.

This study was designed to replicate and extend past research examining the impact of the serotonin transporter gene-linked polymorphic region (5HTTLPR) on neural activation during emotional processing. Six women with at least one short allele were compared to six age-matched women with long/long alleles of the 5HTTLPR. Participants were shown 36 positive and 36 negative slides from the International Affective Picture Set, while functional images were acquired using a 4-T magnetic resonance imaging scanner. Although we were unable to replicate past research demonstrating relatively increased amygdala activation among individuals with an "s" allele to negative stimuli, women with an s allele evidenced decreased left fusiform gyrus activation to positive emotional stimuli (as expected). We suggest that women with a short allele may be either less attentive or less "expert" with regard to positive emotional stimuli, and ideas for future research are presented.

MR imaging-guided vascular procedures using CO2 as a contrast agent.

OBJECTIVE: The purpose of this study was to test the use of CO(2) as a black blood contrast agent for MR imaging-guided vascular procedures in an animal model. MATERIALS AND METHODS: Repeated intraarterial CO(2) injections were performed through a catheter located in the aorta and the renal arteries of three fully anesthetized pigs. Real-time images were acquired using a steady-state free precession sequence. RESULTS: During the CO(2) injections, the bright blood in the aorta and the main renal artery was totally replaced, and this procedure resulted in an immediate, statistically significant signal loss in the vessel lumen. In more peripheral vessels, CO(2) improved the vessel conspicuity substantially. Confirmation of vessel patency distal to the catheter tip position was possible. CONCLUSION: The use of carbon dioxide in combination with a bright blood MR imaging sequence improves vessel conspicuity and provides immediate information about blood flow distal to the catheter. This technique may be used to facilitate MR imaging-guided intravascular procedures.