Disease relevance of CI-1033

• In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection [1].
• Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading [1].
• Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer [2].
• Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best [3].
• PURPOSE: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability [4].

High impact information on CI-1033

• Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization [1].
• PATIENTS AND METHODS: This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy [2].
• PURPOSE: To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells [2].
• The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux [3].
• Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump [3].

Chemical compound and disease context of CI-1033

• The purpose of this study was to determine the effects of a novel small molecule ErbB tyrosine kinase inhibitor, CI-1033, in combination with ionizing radiation on breast cancer cell growth and survival [5].
• Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment [6].

Biological context of CI-1033

• Furthermore, tumors that depend on ErbB receptor signaling for survival and exhibit activated p38 in the basal state may be susceptible to apoptosis by CI-1033 as a single agent [7].
• Treatment of BT474 cells with CI-1033 inhibited both the phosphorylation of Akt and MAPK and resulted in a 47% apoptotic fraction [7].
• Treatment with the pan-ErbB inhibitor CI1033 and the anti-EGF receptor (EGFR) antibody C225 demonstrated that ligand-mediated activation of EGFR is required for SUM149 cell proliferation [8].
• Phase 1 clinical and pharmacokinetics evaluation of oral CI-1033 in patients with refractory cancer [9].
• At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation [4].

Anatomical context of CI-1033

• EXPERIMENTAL DESIGN: We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo [10].
• The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells [10].

Associations of CI-1033 with other chemical compounds

• Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline [6].
• In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized [11].

Gene context of CI-1033

• In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated [12].
• In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models [12].
• Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector [3].
• METHODS: Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6-8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [(18)F]fluorodeoxyglucose, [(18)F]fluoro-L: -thymidine, [(18)F]fluoro-azoazomycinarabinoside or [(18)F]fluoromisonidazole [6].
• Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment [6].

Analytical, diagnostic and therapeutic context of CI-1033

• Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively [3].
• In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38 [3].
• Two compounds were evaluated against A431, H125, and MCF-7 xenografts in nude mice but were inferior in these assays to the clinical trial compound CI-1033 [13].
• Thus, CI-1033, which is currently undergoing phase I clinical trials, holds significant potential for use in a broad range of solid tumors [14].
• In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033 [15].

References