Authors: Jörgen Carlsson Veronika Eriksson Bo Stenerlöw Hans Lundqvist
Publish Date: 2006/05/23
Volume: 33, Issue: 10, Pages: 1185-1195
Abstract
Five tumour cell lines U373MG and U118MG gliomas HT29 colon carcinoma A431 cervical squamous carcinoma and SKBR3 breast cancer were used An experimental model with 105 tumour cells in each sample was irradiated with low dose rate beta particles The criterion for successful treatment was absence of recovery of cells during a followup period of 3 months The initial dose rates were in the range 01–08 Gy/h and the cells were continuously exposed for 1 3 or 7 days These combinations covered dose rates and doses achievable in targeted radionuclide therapyContinuous irradiation with dose rates of 02–03 and 04–06 Gy/h for 7 and 3 days respectively could kill all cells in each tumour cell sample These treatments gave total radiation doses of 30–40 Gy However when exposed for just 24 h with about 08 Gy/h only the SKBR3 cells were successfully treated all the other cell types recovered There were large cell typedependent variations in the growth delay patterns for the cultures that recovered The U118MG cells were most resistant and the U373MG and SKBR3 cells most sensitive to the treatments The HT29 and A431 cells were intermediateThe results serve as a guideline for the combinations of dose rate and exposure time necessary to kill tumour cells when applying low dose rate beta irradiation The shift from recovery to “cure” fell within a narrow range of dose rate and exposure time combinationsMany types of tumour overexpress cell surfaceassociated antigens or receptors suitable as targets for radionuclide therapy and many types of targeting agent have been suggested or are already being applied for such therapy This therapy is currently employed for lymphomas 1 2 using radiolabelled antibodies and also for neuroendocrine 3 4 5 and paediatric tumours 6 7 using radiolabelled somatostatin analogues and metaiodobenzylguanidine mIBG respectively In the majority of these cases beta emitters such as 90Y 131I and 177Lu have been applied The results have so far essentially shown palliative effects 1 8 9 10 11 12 and there is hope that combinations of beta particle emitters eg 90Y and 177Lu will improve the therapy results 13The cellkilling capacity of low LET radiation ie photons and electrons is well known when applying high dose rates typically 05–20 Gy/min as in external radiotherapy 14 15 However the extensive experimental and clinical knowledge on the effects of external radiotherapy can be deployed to only a limited extent in understanding the effects of radionuclide therapy A major difference is that the dose rate in radionuclide therapy is at least two orders of magnitude lower than in external radiotherapy 10 16 17 18 19 The lower dose rate allows for DNA repair and repopulation during the radiation exposure which is not the case during high dose rate exposures Basic radiobiological studies have shown that low dose rates in the range of 01–10 Gy/h give a much lower biological effect per dose unit than high dose rates in the range 05–20 Gy/min 15 17 20 21 It is also known that an inverse dose rate effect exists in that dose rates of 02–04 Gy/h can give more cell kill than dose rates in the range 07–10 Gy/h 15 22Only crude estimates can be made from previous experiments to elucidate which combinations of low dose rate and exposure time can cure a metastasis containing for example 105 cells Cell survival has most often been analysed after a cell cloning 1–2 weeks after the radiation exposure For example a total dose of about 30–50 Gy given with 01–10 Gy/h seems necessary to decrease the single cell survival probability to 10−5 23 24 and thereby give a reasonable chance of killing 105 tumour cells Furthermore targeted radionuclide therapy is complicated since it is not enough only to consider the macroscopic dose concept different cellular and intracellular distributions of radionuclides can give different biological effects although the macroscopic dose is the same 25 26One way to obtain solid information on which combinations of low dose rate and exposure time can give curative treatments with beta particles which also is lowLET radiation is of course through experiments and clinical trials In this study we used an experimental model with the criterion that the low dose rate beta radiation must kill all 105 tumour cells in a culture dish in order to simulate a successful treatment The followup period was 3 months
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