Key Words: Ro 40-5967--calcium antagonists-hypertension-coronary heart diseaseCalcium antagonists are now widely used for the treatment of angina pectoris and hypertension (for review, see ref. 25). Despite different chemical structures, they all inhibit the slow Ca2+ inward current (7,15). Three main classes of calcium antagonists have been described: dihydropyridines, represented by nifedipine; phenylalkylamines, represented by verapamil; and benzothiazepines, represented by diltiazem. Each of these compounds has its own advantages and disadvantages. Dihydropyridine-type calcium antagonists are very potent peripheral vasodilators and can therefore produce headache, ankle edema, and reflex tachycardia (24). Verapamil has a very potent negative inotropic effect (29) that makes this compound dangerous in patients with a compromised myocardium (8,27). Diltiazem is also negatively inotropic, can produce severe bradycardia, and has also been shown to increase the mortality of patients with prior myocardial infarction and clinical signs of heart failure (30).Finally, all existing calcium antagonists (except the novel dihydropyridine, amlodipine) have a poor bioavailability due to a large first-pass effect and a rather short half-life requiring slow-release formulation for once-a-day dosing. Therefore, the purpose of the calcium antagonist program at F. Hoffmann-La Roche Ltd, Basel was to find a compound with the following properties: (a) high bioavailability; (b) long half-life, allowing once-a-day dosing; (c) lack of biologically relevant negative inotropism; and (d) no strong peripheral vasodilation in normotensive subjects.Ro 40-5967, a novel calcium antagonist, which was selected in animal experiments, fulfilled these criteria. The first clinical studies confirmed the preclinical findings. CHEMISTRYThe chemical name of Ro 40-5967 (see Fig. 1) is (lS,2S)-2-(2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl)-6-fluoro-1,2,3 ,Ctetrahydro-1 -isopropy1-2-naphthylAddress conespondence and reprint requests to Dr.
BACKGROUND Hypoxia-inducible factor 1α (HIF-1α) is a gene that regulates tumor survival, neovascularization and invasion. Overexpression of HIF-1α correlates with poor prognosis in hepatocellular carcinoma (HCC). RO7070179 is a HIF-1α inhibitor that decreases HIF-1α mRNA and its downstream targets, it could be a potential treatment in HCC. AIM To evaluate safety and preliminary activity of RO7070179 in patients with previously treated HCC, with focus on a patient with prolonged response to RO7070179. METHODS In the preclinical study of RO7070179 in a HCC xenograft model, the mice were separated into 4 groups with each group received doses of 0, 3, 10 and 30 mg/kg for total 10 doses. HCC patients who failed at least one line of systemic treatment, received RO7070179 as a weekly infusion, each cycle is 6 wk. We evaluated the safety and HIF-1α mRNA levels of RO7070179. RESULTS Preclinical evaluation of RO7070179 in orthotopic HCC xenograft model showed no significant differences in HCC tumor weight between the 3 and 10 mg/kg groups. However, dose of 10 mg/kg of RO7070179, has shown 76% reduction of the amount of HIF-1α mRNA in HCC tissue. In the phase 1b study of RO7070179 in previously treated HCC patients, 8 out of 9 were evaluable: 1 achieved PR and 1 SD. The patient with PR responded after 2 cycles treatments, which has been maintained for 12 cycles. This patient also showed reduction in perfusion of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after 1 cycle of treatment. After 1 cycle of treatment, both patients with PR and SD showed decrease in HIF-1α mRNA at the root of biopsies (each biopsy was divided into 2 specimens, the tip and the root). CONCLUSION RO7070179 can reduce HIF-1α mRNA level in HCC patients with SD or PR. It is well tolerated at 10 mg/kg, with transaminitis as the dose of increased toxicity. This study indicates that RO7070179 might benefit HCC patients, and an early signal for clinical benefit can potentially be predicted through changes in either mRNA level or DCE-MRI within 1 cycle of therapy.
Summary The early and late morphological changes induced in rat bladder urothelium by intravesicular administration of the alkylating agents methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) are described. In the short-term, both compounds produced dose-related toxic damage followed by a regenerative hyperplasia of the urothelium. At any given dose-level, the effects of MMS were more severe than those of EMS. Previous experiments in this laboratory established that the alkylating agent N-methyl-N-nitrosourea (MNU) is both a powerful hyperplastic agent and a bladder carcinogen when administered by intravesicular instillation (Hicks and Wakefield, 1972). This finding has provided a useful model system in which the mechanisms of carcinogenesis and the effects of modulators can be explored (Hicks, 1980;Hicks et al.,1975Hicks et al., , 1978Severs et al., 1982). Intravesicular instillation of two other alkylating agents, viz. methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS) in the short-term produced toxic damage followed by urothelial hyperplasia (Wakefield & Hicks, 1974
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