Polyamine analogues inhibit neuroblastoma cell growth

Abstract: Abstract Neuroblastoma is a highly malignant neoplasm found in children. Although children with high-risk neuroblastoma respond to chemotherapy, relapses are common and an estimated long-time survival prognosis is approximately 15%. Thus, there is a tremendous need for new chemotherapeutic drugs for the treatment for neuroblastoma. Polyamines are needed for cell proliferation and cell survival. Thus, polyamine pool depletion is considered as a cancer intervention strategy. One means to achieve polyamine pool depletion is by treating with polyamine analogues. Polyamine analogues have shown to have antineoplastic activities in a variety of experimental tumour systems and are therefore tested in clinical trials. Polyamine analogues could be potential new chemotherapeutic agents for treatment of neuroblastoma. The general aim of my thesis was to investigate how polyamine analogue treatment would affect neuroblastoma cell proliferation and survival. Three neuroblastoma cell lines, chosen because of their different genetic backgrounds, were treated with the three polyamine analogues PG-11047, PG-11093, and N1,N11-diethylnorspermine. When the cells were treated with polyamine analogue for one treatment cycle, SH-SY5Y and IMR-32 cells, containing wild type p53, were more sensitive than LA-N-1 cells, containing mutated p53. However, when the cells were treated with PG-11047 for repeated cycles, in a manner more resembling the treatment schedule used for patients, the IMR-32 and LA-N-1 cells, containing MYCN amplification, were more sensitive than SH-SY5Y cells. In fact SH-SY5Y cells appeared to develop resistance to PG-11047 while the MYCN-amplified cell lines died. This work shows the importance of treating cell lines with repeated treatment cycles to obtain a better picture of the fate of the cells. Most importantly, the results show that polyamine analogue treatment may be very effective in aggressive MYCN-amplified neuroblastoma. The polyamine analogue PG-11047 is used in clinical trial and shows low general toxicity and may be used for treatment of children with MYCN-amplified neuroblastoma.