Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant (MDR) cell lines and tumors where paclitaxel fails. In the current account, we focus on the relationship between epothilone and paclitaxel in the context of tumors with multiple drug resistance. The epothilone analogue Z-12,13-desoxyepothilone B (dEpoB) is >35,000-fold more potent than paclitaxel in inhibiting cell growth in the MDR DC-3F/ADX cell line. Various formulations, routes, and schedules of i.v. administration of dEpoB have been tested in nude mice. Slow infusion with a Cremophor-ethanol vehicle proved to be the most beneficial in increasing efficacy and decreasing toxicity. Although dEpoB performed similarly to paclitaxel in sensitive tumors xenografts (MX-1 human mammary and HT-29 colon tumor), its effects were clearly superior against MDR tumors. When dEpoB was administered to nude mice bearing our MDR human lymphoblastic T cell leukemia (CCRF-CEM/paclitaxel), dEpoB demonstrated a full curative effect. For human mammary adenocarcinoma MCF-7/Adr cells refractory to paclitaxel, dEpoB reduced the established tumors, markedly suppressed tumor growth, and surpassed other commonly used chemotherapy drugs such as adriamycin, vinblastine, and etoposide in beneficial effects.

Military and government applications of human-machine communication by voice.

This paper describes a range of opportunities for military and government applications of human-machine communication by voice, based on visits and contacts with numerous user organizations in the United States. The applications include some that appear to be feasible by careful integration of current state-of-the-art technology and others that will require a varying mix of advances in speech technology and in integration of the technology into applications environments. Applications that are described include (1) speech recognition and synthesis for mobile command and control; (2) speech processing for a portable multifunction soldier's computer; (3) speech- and language-based technology for naval combat team tactical training; (4) speech technology for command and control on a carrier flight deck; (5) control of auxiliary systems, and alert and warning generation, in fighter aircraft and helicopters; and (6) voice check-in, report entry, and communication for law enforcement agents or special forces. A phased approach for transfer of the technology into applications is advocated, where integration of applications systems is pursued in parallel with advanced research to meet future needs.