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Altersbioscience.com

A novel N-oxide drug, AQ4N, demonstrates in vitro cytotoxicity
on solid tumor and hematopoietic tumor cell lines
Susan E. Alters*, Alvin Wong, and Jeffrey L. Cleland Abstract
Cytotoxicity Assessment
Relative Potency AQ4N/AQ4
Tumor Line Type AQ4 (IC50) AQ4N (IC50)* Standard STD/AQ4***
AQ4N (1,4 bis{2-(dimethylamino)ethylamino}-5,8-hydroxyanthracene-9,10-dione bis N-oxide) is designed to have little or no toxicity until selectively bioreduced in vivo by hypoxic cells to AQ4 (reduced AQ4N), a highly potent DNA topoisomerase II inhibitor.
Cytotoxicity of AQ4 has been investigated by MTT assay on a panel of solid and hematopoietic tumor cell lines. The IC50 of AQ4 ranged from 0.4-1.6 µM on the pancreatic tumor lines; the IC50 of 0.4 µM on Panc-1 was four-fold lower than that of the standard agent, gemcitabine. On the colon carcinoma line, HT-29, AQ4 demonstrated an IC50 of 0.3 µM, comparable to SN38, and ten-fold better than oxaliplatin. On glioma lines U118, U251, U87, IC50’s of AQ4 were 0.3, 0.6, 1.6 µM respectively. AQ4 also demonstrated potent cytotoxicity on a panel of lymphoma and leukemia tumor cell lines. The IC50 of AQ4 was 0.2 nM on Namalwa human lymphoma, 10 µM and 1.5 µM on HL60 and Molt-4 human leukemia, and 1.2 nM and 10 nM on L1210 and P388 murine leukemia; on each of these tumor lines cytotoxicity was greater than that seen with doxorubicin. AQ4N had significant activity in Namalwa, MOLT-4, KGa1, K562, L1210 and P388, suggesting a non-hypoxia-related mechanism of bioreduction in these hematologic lines. Potent AQ4 activity was also seen on the human multiple myeloma lines, RPMI8226 and ARH-77. The potent in vitro activity of AQ4 is currently being followed up with in vivo efficacy studies of Background
• AQ4N is a N-oxide prodrug designed to be bioreduced under hypoxic conditions • Previous studies have shown that AQ4N undergoes two consecutive 2 electron reductions to yield AQ4, a potent topoisomerase II inhibitor (see Figure; Patterson, AQ4 (IC50; µM)
• Bioreduction of AQ4N is catalyzed by cytochrome P450 enzymes 1A1, 1B1, and 3A4 (Patterson, Drug Metab Rev 2002; 34: 581-92) • Work is ongoing to investigate the potential roles of other enzymes in the • AQ4N is currently being studied in several human Phase I studies in the US and • AQ4N is cytotoxic under normoxic conditions • Some cell lines are significantly more sensitive to AQ4N than others, even when accounting Bioreduction
• AQ4 cytotoxicity is greater than doxorubicin in many of the hematological tumor lines and • The mechanism of AQ4N cytotoxicity under normoxic conditions is unknown Blue = AQ4N activity and/or AQ4 more active than standard • The broad spectrum of activity observed for AQ4N and AQ4 is supportive of AQ4N All results represent 24 hr drug exposure followed 48 hrs later by MTS assay for live cells (range nM to µM) monotherapy in several oncology indications.
* Study done under normoxic conditions only** NA = not active; IC50 > 100 µM *** Ratio of IC50 values for Standard and AQ4 (Larger value indicates AQ4 more potent than standard under • AQ4N in vivo activity in solid and hematopoietic tumor models (AACR 2005) • Mechanism of action studies with enzyme inhibitors • AQ4N biodistribution in solid tumor model (AACR 2005)

Source: http://altersbioscience.com/PresentationsPDFs/ExpBiol_2005.pdf

Lf021203-13

Rapid City Department Of Fire & Emergency Services Ambulance Rate Structure: This document details the proposed new ambulance rate schedule to be utilized by the Rapid City Department of Fire and Emergency Services. Its content is tentative pending final approval by the Emergency Medical Services Oversight Committee. In considering a new rate structure many factors had to be considered. The

Microsoft word - 4.11.2011_produkliste aktuell Österreich-lizenz , spak,-1.…

Liste der ÖKOWELLNESS-Spezialitäten Lieferbare Produkte ab September 2011 mit Rezepten und typgerechter Zuordnung. Hergestellt von den Firmen Peter SPAK GmbH Wien und anderen lizenzierten Herstellern in Manufaktur-Qualität. Alle Produkte sind aus kontrolliert ökologischem Anbau. Kontrollnummer: AT BIO-301 Kontrollstelle der zentralen Entwicklung und für einzelne Produkte ÖKOWELLNE

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