The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity.

The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant (K value) of 5000 M(-1). This association constant is significantly higher than the K(DLPC) value observed for camptothecin (K(DLPC) value of 110 M(-1)). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 microM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37 degrees C. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898; J. Med. Chem. 43 (2000) 3970]. Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development.

Selective attention in perceptual adjustments to voice.

The effects of perceptual adjustments to voice information on the perception of isolated spoken words were examined. In two experiments, spoken target words were preceded or followed within a trial by a neutral word spoken in the same voice or in a different voice as the target. Over-all, words were reproduced more accurately on trials on which the voice of the neutral word matched the voice of the spoken target word, suggesting that perceptual adjustments to voice interfere with word processing. This result, however, was mediated by selective attention to voice. The results provide further evidence of a close processing relationship between perceptual adjustments to voice and spoken word recognition.

Telephone-Assessed Mental State.

In 30 patients with Alzheimer's disease (AD), we compared performance on a brief Telephone-Assessed Mental State (TAMS) examination with performance on standard cognitive instruments administered face to face. TAMS scores correlated strongly with scores on both the Mini Mental State Examination (rho = 0.81) and the Alzheimer's Disease Assessment Scale (rho = -0.80).