Bcl-2 antisense oligonucleotides in the treatment neoplastic diseases in children

A. Chybicka, R. Chaber, J. Toporski

Wroclaw Medical University, Department of Pediatric Oncology and Hematology.

Mitochondrial protein bcl-2 is an important inhibitor of apoptosis. Blocking expression of bcl-2 gene by antisense oligonucleotides (AS-ODN) administration may result with lower production of blc-2 protein what makes neoplastic cells more sensitive to chemotherapy. Nine children with malignant diseases entered the study. Boys/girls - 5/4; age - 4-15 years; ALL-pre B --- 5; ALL-T --- 1; AML --- 1; LCAL --- 1; Nephroblastoma --- 1; Post auto-PBSCT - 2 Antisense oligonucleotide anti bcl-2 (18-mer) was modified by thioester group supplementation. It was administrated as a continuous 24-hour infusion via central vein catheter at dose of 14.5 --- 67,0 mg/m2/day. Duration of the treatment was 10 days. Chemotherapy was combined with antisense infusion. The first protocol was based on Fludarabine and Cytarabine (3 patients), the second on Topotecan and Cyclophosphamide (3 patients). Three patients were treated according individually adjusted chemotherapy. If treatment based on those protocols was not effective, AS-ODN were given with Paclitaxel and Doxorubicin (3 patients) or Vinblastin (1 patient). G-CSF was administrated in 5 cases. There were no side effects during AS-ODN administration. The expression of bcl-2 protein in malignant cells was measured in four patients (FACS analysis). The decreasing expression of bcl-2 protein more than 1/3 of the initial value was detected in two cases. Complete remission was achieved in one patient with LCAL --- stable remission is observed for 20 weeks. Five months after the treatment 4 patients are alive (3 with disease) and 5 died due to progressive disease. he preliminary observation showed that antisense administration is safe and has no clinically relevant side effects. Higher dose and repeated AS-ODN infusion seems to be necessary to achieve better disease control.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Immunotherapy.