Susan A. Coughlin

Tumor Models and the Discovery and Secondary Evaluation of Solid Tumor Active Agents

AbstractEach independently arising tumor is a separate and unique biologic entity with its own unique histologic appearance, biologic behavior, and drug response profile. Thus, in drug discovery, no single tumor has been a perfect predictor for any other tumor. For this reason, new agents are evaluated in a variety of tumor models which is known as breadth of activity testing. In recent years, human tumors implanted in athymic nude mice and SCID mice have also become available for breadth of activity testing. In studies carried out in these laboratories, it was found that 10 human tumors metastasized in the SCID mice, but failed to metastasize in nude mice. In addition, tumor growth and tumor takes were superior in the SCID mice. The strengths and weaknesses of xenograft model systems are discussed. For example, most human tumor xenograft models are excessively sensitive to alkylating agents as well as to a new class of DNA binders (XE840 and XP315). Using human tumor models that are the least sensitive t...

The antitumor activity of novel pyrazoloquinoline derivatives

Abstract Mammalian topoisomerase II inhibition activity has been identified in a series of novel pyrazoloquinoline derivatives; potency for two analogues containing cyclohexyl groups at the 2-position was comparable to the reference agents, mAMSA and VP-16. In several instances, topo II inhibition translated to a high level of in vitro cytotoxicity and murine antitumor activity.

Mechanism of action and antitumor activity of (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridol [1,2,3-de]-[1,4]benzothiazine-6-carboxylic acid (WIN 58161)

(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (WIN 58161) is an enantiomerically pure quinolone with outstanding bacterial topoisomerase II (DNA gyrase, EC 5.99.1.3) inhibitory and antibacterial activity. Unlike most quinolones, WIN 58161 also exhibits significant inhibitory activity against mammalian topoisomerase II (EC 5.99.1.3). DNA gyrase and topoisomerase II inhibitory activities are enantioselective. Consequently, WIN 58161 and its enantiomer (WIN 58161-2) provide useful tools to probe the contribution of topoisomerase II inhibition to the mechanism of cytotoxicity of quinolones and the potential utility of quinolone-topoisomerase II inhibitors as antitumor agents. WIN 58161 inhibited both highly purified Escherichia coli DNA gyrase and HeLa cell topoisomerase II by the promotion of enzyme-DNA covalent complexes. WIN 58161 did not bind stably to DNA via intercalation and did not enhance the formation of topoisomerase I (EC 5.99.1.2)-DNA covalent complexes. At drug concentrations that are cytotoxic to P388 murine leukemia cells, WIN 58161 promoted intracellular DNA single-strand breaks (SSBs) that exhibited the hallmarks of being mediated by topoisomerase. DNA fragments were complexed with protein, and SSBs were readily resealed at 37 degrees following drug removal. WIN 58161-2 was neither cytotoxic nor did it promote intracellular SSBs in P388. These observations suggest that the mechanism of cytotoxicity of WIN 58161 is predominantly, if not exclusively, a result of topoisomerase II inhibition. When studied in tumor-bearing mice, WIN 58161 exhibited a significant antitumor effect against each of five tumors tested, whereas neither toxicity nor antitumor activity was observed with WIN 58161-2. We conclude from these studies that WIN 58161 represents the prototype of a novel chemical class of topoisomerase II inhibitor with potential clinical utility in treating cancer.

3-BENZYL-QUINOLONES: NOVEL, POTENT INHIBITORS OF MAMMALIAN TOPOISOMERASE II

Abstract Replacement of the 3-carboxy group of quinolone topoisomerase II inhibitors by hydroxy substituted benzyl groups resulted in potent topoisomerase II inhibitors. The 2,6-dihydroxybenzyl analog, Win 64593, had a topo II EC 50 of 96 nM and had potent in vitro cytotoxicity as well as murine antitumor activity.

Cyclic variations of SR 233377 (WIN 33377) and effects on antitumor activity

Abstract Novel derivatives of SR 233377 ( 1 , WIN 33377) where a pyrazolo ring fusion has been incorporated at the 1- and 9-positions of the thioxanthone ring displayed outstanding in vivo efficacy against the murine solid tumor Panc 03 (T/C values of 0% with log cell kill ⩾ 2.0). No relationship between structure and Panc 03 activity was observed because all analogues studied were highly active.

Potent mammalian topoisomerase II inhibitors: 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-substituted-quinolines

A series of novel 4-substituted-1,4-dihydro-quinolines 3 were prepared and found to exhibit moderate to excellent mammalian topo II inhibitory activity. Among the compounds prepared, in general, the nitrogen analogues are the most active compounds and the sulfur analogue is the least active one.

Relationship of structure of bridged (2,6-dimethyl-4-pyridinyl)quinolones to mammalian topoisomerase II inhibition☆

Abstract Several enantiomerically pure (2,6-dimethyl-4-pyridinyl)quinolones, previously shown to be potent inhibitors of bacterial DNA gyrase, exhibit topoisomerase II inhibitory activity. Among these and other analogues, topoisomerase II inhibitory potency was found to be a sensitive function of the size and substitution of the bridge spanning the 1- and 8-positions of the quinoline ring. The 6-fluoro group was required for activity.