Taxol plus recombinant human granulocyte-colony stimulating factor as initial and as salvage chemotherapy for metastatic breast cancer: a preliminary report

Twenty-eight patients received Taxol as their first chemotherapy for stage IV breast cancer. An additional 51 patients with extensive prior exposure to other chemotherapeutic agents received Taxol as salvage therapy. We found significant activity for the drug in both situations, as well as a strong clinical suggestion of non-cross-resistance with doxorubicin. An excellent response in previously irradiated skin was noted in one case. The routine use of recombinant human granulocyte-colony stimulating factor seemed to ameliorate some of the dose-limiting toxicity of neutropenia. Other toxicity was mild to moderate in most cases. With further development, Taxol should play a significant role in the systemic management of breast cancer.     

Archive contributions to a molecular phylogeography of the toad Bufo calamita in Britain

A complete phylogeographic analysis of any species requires sampling throughout its biogeographical range. In the case of the natterjack toad Bufo calamita in Britain, recent local extinctions have left substantial areas of its historical range without extant populations. We therefore obtained tissue samples of archived Bufo calamita from four museums in the United Kingdom. A range of tissues (tongue, liver, skin, lung, and larval tail) was sampled from a total of 33 individual animals. DNA was extracted and eight polymorphic microsatellite loci were scored. One or more loci were amplified successfully from 27 individuals, and sufficient data were obtained from regions with few or no surviving populations to supplement a phylogeographic analysis based on extant populations.     

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.     

3D time-resolved contrast-enhanced MR DSA: advantages and tradeoffs

To test whether renal V1-receptors selectively influence blood flow in the renal medulla, we compared the effects of infusion of [Phe2,Ile3,Orn8]vasopressin (3-30 ng/kg/min) by the intravenous, renal arterial, and renal medullary interstitial routes in anesthetized rabbits. Intravenous [Phe2,Ile3,Orn8]vasopressin (30 ng/kg/min) reduced renal medullary perfusion (MBF) by 36 +/- 5% but did not significantly affect cortical perfusion (CBF). MBF was also reduced with the renal arterial (35 +/- 5%) and renal medullary interstitial (40 +/- 7%) routes but, in contrast to the intravenous infusion, CBF was also reduced, by 21 +/- 3% and 15 +/- 3%, respectively. Urine flow and sodium excretion were increased by [Phe2,Ile3,Orn8]vasopressin, and with direct intrarenal administration, this effect was similar for both the infused (left) and noninfused (right) kidneys. After a 20-min renal medullary interstitial infusion of [3H]norepinephrine, radiolabel concentration was approximately fivefold greater in the left medulla than in the left cortex. We conclude that [Phe2,Ile3,Orn8]vasopressin acts on V1-receptors to alter regional kidney blood flow and tubular salt and water handling. The V1-receptors involved are almost certainly within the kidney itself, but given the contrasting effects of the different infusion routes on MBF and CBF, we cannot exclude the possibility that some of the observed effects of [Phe2,Ile3,Orn8]vasopressin are mediated by activation of extra-renal V1-receptors.     

Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis

Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.