semaxinib and Carcinoma

One of the most studied pro-angiogenic factors involved in the development of colorectal cancer is the vascular endothelial growth factor (VEGF). The small molecule tyrosine kinase inhibitor semaxanib (SU5416) is one of the several agents targeting the VEGF signaling pathway, and its development centered mostly in the treatment of colorectal cancer.. We designed and conducted an NCI-sponsored trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of semaxanib given twice weekly in combination with weekly irinotecan in patients with advanced colorectal cancer who had failed at least one prior treatment. The irinotecan dose was fixed at 125 mg/m(2) given weekly for 4 weeks followed by 2 weeks of rest. Patients with prior pelvic irradiation received a reduced dose of 100 mg/m(2). The semaxanib dose was escalated, going from 85 to 110 mg/m(2) and finally to 145 mg/m(2).. Ten patients were treated in our study and all were evaluable for toxicity. There were no drug-related Grade 4 toxicities. There was one episode of Grade 3 headache and one episode of Grade 3 vomiting. The most common Grades 1 and 2 toxicities included diarrhea, abdominal cramping, anemia and nausea. Nine patients completed at least one 6 week cycle of treatment and were considered evaluable for response. Among those nine, two had a partial response, three had stable disease and four had progressive disease after the first cycle.. Both irinotecan and semaxanib could be given at their full single-agent recommended doses without significant toxicity, and the combination showed signs of clinical activity. However, owing to discouraging results from Phase III trials, it is unlikely that this combination will be further explored.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Indoles; Irinotecan; Male; Maximum Tolerated Dose; Middle Aged; Protein Kinase Inhibitors; Pyrroles; Treatment Outcome

SU5416 is reported to be a selective inhibitor of vascular endothelial growth factor, and it has metwith limited success in the clinic. In the present study, we investigated whether SU5416 could augment cisplatin-induced cytotoxicity in human ovarian cancer cells. When used as a single agent, 2-h exposures to SU5416 were not harmful to the cells up to doses of 100 microM. For 48-h exposures, the SU5416 IC20 and IC50 were 17 and 34 microM, respectively. When used with cisplatin, the effect of SU5416 was sequence dependent. SU5416 given first was subadditive, whereas cisplatin given first was supraadditive. Cisplatin was given as a 1-h exposure. Augmented cisplatin cytotoxicity was seen with 2-h exposures to SU5416 at doses of 17-34 microM. This was associated with a decrease in cisplatin-DNA adduct repair, as measured by atomic absorbance spectrometry. Treatment of the ovarian carcinoma cells with SU5416 was also associated with a reduced expression of ERCC-1 protein and c-jun mRNA, as well as a decrease in c-Jun and JNK activities. We conclude that SU5416 can be used to augment cisplatin-induced cell killing at doses that are non-toxic. This effect may occur through direct or indirect reduction of the activity of AP-1 and DNA repair.

Topics: Carcinoma; Cisplatin; DNA Damage; DNA Repair; DNA-Binding Proteins; Endonucleases; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Indoles; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Proteins; Proto-Oncogene Proteins c-jun; Pyrroles; Transcription Factor AP-1; Tumor Cells, Cultured