Abstract #3608: Phase I study of escalating doses of 5-FU and arsenic trioxide (As2O3) in patients with refractory metastatic colorectal carcinoma
Authors: Subbarayan Pochi, Yipsel Ramos, Anthony Fernandez, Dmitry Mezentsev, Parvin Ganjei-Azar, Ishildinha Reis, Kelvin Lee, Bach Ardalan
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Introduction: In vitro, prolonged exposure of colon cancer cells to 5-FU induces resistance and is associated with increased synthesis of thymidylate synthase (TS). 5-FU resistance is well correlated with the over expression of intratumoral TS mRNA which if down regulated may reverse 5-FU resistance. Earlier we demonstrated that arsenic trioxide (As2O3) significantly down regulated TS in vitro as well as in patients (pts) thereby re-sensitizing tumor cells to 5-FU. Methods: In this ongoing Phase I clinical trial, a treatment cycle consisted of four weeks of therapy and one week of rest. On days one through five, 8, 11, 15 and 22, the pts received a 4-hour As2O3 infusion. On days 8, 15 and 22, pts were administered a 24-hour infusion of 5-FU/ Leucovorin To date, 13 pts with refractory metastatic colorectal carcinoma have been enrolled. Thirty one treatment cycles have been administered to 11 pts. One pt was removed from the study due to treatment unrelated fracture and one pt was screened out. In the 5-FU dose escalation phase, pt one received 1600 mg/ m2; pt two 2000 mg/m2; pt three 2300 mg/m2; pt four and all the subsequent pts received 2600 mg/m2 of 5-FU. As2O3 was infused at 0.15 mg/kg in pt one through seven and at 0.20 mg/kg in pt eight through 13. One tumor specimen was obtained at pretreatment and the second at the end of the cycle 1. Peripheral blood mononuclear cells (PBMC) were obtained before and during therapy. TS levels were monitored by RT-PCR. Results: The toxicities were as follows: No pt experienced grade 4 toxicities. Grade 3 toxicity: diarrhea (1), neutropenia (1); QTc prolongation (1), fatigue (1), alkaline phosphatase elevation (1). Grade 2 toxicity: anorexia (1), constipation (1), fatigue (2), edema (1), nausea & vomiting (2), AST elevation (1), Anemia (1). Three pts developed herpes zoster (Gr.2) outbreak which resolved with acyclovir. Plasma As2O3 levels ranged from 41 to 157 µg/L. As2O3 suppresses TS transcription: We propose that by down regulating the TS gene expression with As2O3, the 5-FU resistant cells become once again sensitive to 5-FU. Therefore, we measured TS mRNA levels in eight pairs of tumor tissues and PBMC of all patients. In four out of 8 pts at the end of cycle one, TS levels were reduced by greater than 70% in tumor samples. In three tissue specimens, the post treatment TS levels increased and in one it remained unchanged. TS levels were down regulated in all the PBMC samples analyzed. Conclusion: 1) 0.2 mg/kg of As2O3 and 2600 mg/ m² of 5-FU regimen have manageable toxicity. (MTD has not been achieved). 2) As2O3 inhibited TS expression in 50% of the tumor and all the PBMC samples analyzed. Decrease of post treatment TS level in tumor and PBMC samples supports our laboratory hypothesis for the use of As2O3 to overcome 5-FU resistance in tumor cells. This work is supported by NCI grant 1R21CA117116-01A2. 

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3608.