Disease relevance of CI 980

• We have characterized the inhibition of in vitro microtubule assembly by the S (CI 980) and R (NSC 613863) enantiomers, their actions on the cytoplasmic microtubule network of epithelial-like PtK2 cells, and on the cell cycle of different human and murine leukemias and PtK2 cells [1].
• High rates of central nervous system (CNS) toxicity and neutropenia occurred in both minimally and heavily pretreated patients who were treated with CI-980 doses above 3.75 mg/m2/day, which is the maximum tolerated dose and the recommended dose for additional evaluations [2].
• CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation [3].
• Phase II study of CI-980 (NSC 635370) in patients with previously treated advanced soft-tissue sarcomas [4].
• CI-980 in advanced melanoma and hormone refractory prostate cancer [5].

High impact information on CI 980

• Although the interactions of CI 980 with microtubules in vitro are not very different from other drugs, it is a most potent cellular microtubule and mitotic inhibitor [1].
• Inhibition of microtubules and cell cycle arrest by a new 1-deaza-7,8-dihydropteridine antitumor drug, CI 980, and by its chiral isomer, NSC 613863 [1].
• CI-980 is a chemotherapeutic agent currently in Phase II trials that arrests cellular division by binding to tubulin [6].
• CI-980 (NSC 613862) is one of a novel class of 1,2-dihydropyrido[3, 4-b]pyrazines that inhibits tubulin polymerization, presumably by binding to the colchicine binding site of tubulin [2].
• Kinetics of association and dissociation of two enantiomers, NSC 613863 (R)-(+) and NSC 613862 (S)-(-) (CI 980), to tubulin [7].

Biological context of CI 980

• 7. It is concluded that in guinea-pig papillary muscles, CI-980 produces a use-dependent inhibition of Vmax and a reverse use-dependent prolongation of the ventricular action potential, thus exhibiting class I and class III antiarrhythmic actions, respectively [8].
• CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site and inhibits the polymerization of tubulin and blocks cell cycle progression in mitosis [4].
• 6. The curve relating membrane potential and Vmax was shifted by CI-980 (10(-5) M) in the hyperpolarizing direction by 2.3 +/- 1.1 mV [8].
• Because of its extensive tissue distribution in animals and its favorable activity against multidrug resistant (MDR)-cells compared with other mitotic inhibitors, such as vincristine, we examined the membrane transport properties of CI-980 [9].
• In addition, induction of apoptosis in response to CI-980 correlates with the presence of a functional mitotic checkpoint and the extent of microtubule depolymerization [10].

Anatomical context of CI 980

• Electrophysiological effects of CI-980, a tubulin binding agent, on guinea-pig papillary muscles [8].
• CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein [3].
• We examined CI-980 cytotoxicity in two lung adenocarcinoma cell lines, A549 and A427 [10].
• In canine Purkinje fibers, CI-980 decreased action potential amplitude (APA), Vmax, and conduction velocity and prolonged repolarization [11].
• In preclinical tumor models, CI-980 showed a broad spectrum of activity, including in multi-drug resistant tumor cell lines, with activity at least equal to that of vincristine [12].

Gene context of CI 980

• CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin [13].
• Urine samples must be pretreated with bovine serum albumin (BSA) to minimize the binding of CI-980 to glass and some plastics [14].
• CI-980 and PD 080658, internal standard, were isolated from 2-ml samples of human plasma and urine by solid-phase extraction with Bond-Elut C18 cartridges [14].

Analytical, diagnostic and therapeutic context of CI 980

• Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study [3].
• New compounds in each class of microtubular drugs, docetaxel, as stabilizing agent, and CI 980, as colchicine analog, currently in clinical trials, were tested at high and low concentrations [15].
• In addition, high concentrations of CI-980 decreased the beating rate of spontaneously firing cell cultures [11].
• Determination of the anticancer agent CI-980 in plasma by achiral liquid chromatography on a Pirkle-type stationary phase [16].
• In this phase II study, CI-980, 4.5 mg/m2, was administered as a 24-hour continuous intravenous infusion for 3 consecutive days and repeated every 21 days [17].

References