Promising Antitumor Activity of a Novel Quinoline Derivative, TAS-103, against Fresh Clinical Specimens of Eight Types of Tumors Measured by Flow Cytometric DNA Analysis

Abstract

A novel quinoline derivative, TAS-103 ( Fig. 1), has many attractive biological functions: i) it inhibits both topoisomerase (topo) I and topo II; ii) it stabilizes both topo I-and topo II-DNA cleavable complexes; iii) it shows potent cytotoxic effects in vitro; iv) it shows high antitumor activities against subcutaneously-implanted murine and human tumors in vivo, as well as various lung-metastatic murine tumors. 1)However, it is unclear whether TAS-103 will show the similar level of activity against tumors in patients. In this setting, the chemosensitivity test is expected to show its potential for predicting activity of anticancer agents against human tumors.Various in vitro drug sensitivity tests have been used to assay the responsiveness of tumors to anticancer agents. 2-7)Among various techniques, the colony-forming assay may be the most widely applied in vitro assay for clinical use. 8) In a large study of prospective trials using colony-forming assay, it was shown that true-positive rate was 60% and true-negative rate was 85% based on clinical response. 9) Although this assay seems to be reliable for predicting the clinical response to chemotherapies, it is time-and cost-consuming, laborintensive, and suffers from a low success rate.10) In addition, this assay requires preparations of a single-cell suspension, which renders considerable damage to the tumor cells.We have used direct in vitro measurements of apoptosis as a chemosensitivity test. Two different methods have been employed; morphological examinations of the nuclear damage, such as the chromatin condensation or degradation, 5) and flow cytometric (FCM) analysis of DNA integrity which shows apoptosis as the sub-G1 population.11) The FCM assay Correlations between TAC and PPC were examined for 16 clinically available anticancer agents, and it was found that TAC at 7n (the modified Fibonacci's dose-escalation scheme) of 14 drugs corresponded well with each one-tenth of PPC. By defining a 30% or more reduction in the integrated diploid peak as effective and a 60% or more reduction as definitely effective, TAS-103 at 5 m mg/ml (7n) showed significantly higher effective rates and definitely effective rates than those of all other investigational new drugs, as well as almost all clinically available anticancer agents, against various malignancies, including nonsmall cell lung cancer, brain tumor and renal cancer. These results strongly suggest that TAS-103 will be expected to show excellent antitumor activities against a wide range of human tumors.

Antineoplastic DNA-Binding Compounds: Intercalating and Minor Groove Binding Drugs

“…It was designed to target both topo-I and topo-II, but experiments conducted by Sappal et al (35) showed that the Two newly-synthesised drugs, named TAS-103 and DACA (Figure 4), act as dual topo poisons. TAS-103 is a quinoline derivate expressing remarkable activity against subcutaneously-implanted murine and human tumours in vivo, as well as various lungmetastatic murine tumours (36). Recent studies on TAS-103 in conjunction with various approved antitumour drugs like cisplatin, if applied simultaneously, expressed a synergistic effect, which may prove benefi cial for the treatment of small-cell lung cancer.…”

Dual inhibition: a novel promising pharmacological approach for different disease conditions

“…Dual monoamine oxidase B inhibitors and adenosine A2A receptor antagonists Methylxanthines [26] and (E,E)-8-(4-phenylbutadien-1-yl)caffeine [27] Inflammation Dual cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) inhibitors Flavocoxid [28] and ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-H-pyrrolizine-5-yl) acetic acid [29] Hypertension Dual inhibitors of neprilysin and angiotensin-converting enzyme BMS-182657, [30] MDL-100173 [31] and S21402 (RB105) {N-[2S,3R-(2-mercaptomethyl-1-oxo-3-phenylbutyl)-l-alanine]} [32] Dual inhibitors of the angiotensin II receptor and neprilysin LCZ696 [33] Dual inhibitors of angiotensin-converting and endothelin-converting enzymes CGS 26303 [34] and SLV 306 (Daglutril) [35] Dual vasopressin receptor (V1/V2) antagonists (RWJ-676070) [36] Thrombosis Dual-acting anticoagulant/antiplatelet inhibitors MC45301, MC45308, MC45350, and MC45403 derived from vitamin B6 (pyridoxine) [37] Microbial infections Dual inhibitors of type I and type II DNA topoisomerases Some novel indolyl quinoline analogs [38] Dual inhibitors of b-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) Platencin [39] Viral infections Dual inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H Madurahydroxylactone derivatives [40] Dual inhibitors of 2A and 3C proteases encoded by human rhinoviruses (HRVs) LY343814 [41] Cancer Dual PI3K and mTOR inhibitors PI-103, [42] NVP-BEZ235, [43] WJD008 [44] and BAG956 [45] Dual topoisomerases I and II inhibitors Benzophenanthridine alkaloids, indolocarbazoles and lipophilic bis(naphthalimides), anthraquinones, pyridoindoles, indenoquinolones, acridines, TAS-103, leptosins (Leps) F and C, tafluposide (F 11782) and XR11576 [46][47][48][49][50] Dual inhibitors of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 NVP-AEE788 [51] Dual inhibitors of IkappaB kinase-2 (IKK2) and Fms-like tyrosine kinase 3 (FLT3) AS602868 [52] The new hybrids retain the potent and selective human AChEinhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in-vitr...…”

“…), tafluposide (F 11782), a novel epipodophylloid, and XR11576, a novel phenazine. [46][47][48][49][50] …”

Ethyl 2-amino-4-(3-chlorophenyl)-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylate

“…For the antitumor activity of 4H-naphtho[2,3-b]pyran-5,10dione derivatives, see: Fujimoto (2007); Perchellet et al (2001); Zhan et al (2007). For natural products containing Hnaphtho[2,3-b]pyran-5,10-dione, see: Jassbi et al (2004); Rodriguez et al (2003).…”