11. Antisense oligonucleotides in the treatment after auto – PBSCT of three children with hematological malignancies

Abstract

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 higher chemosensitivity of leukemic cells. C-myb is one of the regulatory proteins of cell cycle. Decreasing its level by antisense oligonucleotides (AS-ODN) may result with decreased leukemic cells proliferation. boys/girls age sex dgn relapse Post auto-PBSCT Patient A 17 years m ALL-T II 1 Patient B 9 years m ALL-preB II 1 Patient C 11 years m NHL-LCAL IV 2 Two boys with relapsed ALL after auto PBSCT and 1 boy with relapsed NHL after second auto PBSCT were treated with AS-ODN. Antisense oligonucleotide anti bcl-2 (18-mer) or anti C-myb was modified by thioester group supplementation. It was administrated as a continuous 24-hour infusion via central vein catheter at dose of 0,5–1,2 mg/kg/day. Duration of the treatment was 10 days. We used three protocols of chemotherapy combined with antisense infusion. The first protocol was based on Fludarabine and Cytarabine (4 patients), the second on Topotecan and Cyclophosphamide (2 patients). If treatment based on those protocols was not effective, infusion of AS-ODN with chemotherapy based on Paclitaxel and Doxorubicin was introduced (2 patients). G-CSF was administrated in each case. No side effects were observed during AS-ODN administration. The expression of bcl-2 protein 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. One complete remission has been achieved lasting 3 months. Two patients died due to disease's progress. The 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.