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T E Wheldon

Publications and source records attributed to T E Wheldon.

At least 19 recordsLinked to original sources
PubMed1995

A radioresistant variant derived from a human neuroblastoma cell line is less prone to radiation-induced apoptosis.

By subjecting radiosensitive human neuroblastoma IMR 32 cells to a regime of fractionated X-irradiation, a radioresistant variant, XRIMR 32, was obtained. Radiation resistance of XRIMR 32 cells was demonstrated by clonogenic and spheroid regrowth delay assays. The XRIMR 32 cultures were phenotypically unstable, with the resistant phenotype being lost after 3 passages in the absence of radiation-selective pressure, but a monoclonal cell line (clone F) was established that maintained its resistance over 35 passages without irradiation. Flow cytometry showed that exponentially growing IMR 32, XRIMR 32, and clone F cells all had very similar cell cycle distributions. Studies of initial DNA damage and repair, using the technique of neutral filter elution, revealed no differences between these lines. Chromosomal damage, as measured by micronucleus frequency following irradiation, was also seen to be very similar. However, studies of apoptosis following irradiation showed significantly higher levels of apoptosis in IMR 32 cells, compared to the resistant lines. This was true at all time points studied between 6 and 42 h after irradiation. p53 status was examined in the IMR 32 and clone F cells. No mutations were detected in exons 5-8 of the cDNA. Both lines showed increased p53 expression after irradiation. These data are consistent with the evolution of cellular resistance as a possible mechanism for the evolution of cellular radioresistance during protracted radiation regimes. However, the molecular mechanism responsible for the increased radioresistance remains to be discovered.

Apoptosis↗
PubMed1995

Optimum combination of targeted 131I and total body irradiation for treatment of disseminated cancer.

PURPOSE: Radiobiological modeling was used to explore optimum combination strategies for treatment of disseminated malignancies of differing radiosensitivity and differing patterns of metastatic spread. The purpose of the study was to derive robust conclusions about the design of combination strategies that incorporate a targeting component. Preliminary clinical experience of a neuroblastoma treatment strategy, which is based upon general principles obtained from modelling, is briefly described. METHODS AND MATERIALS: The radiobiological analysis was based on an extended (dose-rate dependent) formulation of the linear quadratic model. Radiation dose and dose rate for targeted irradiation of tumors of differing size was in part based on microdosimetric considerations. The analysis was applied to several tumor types with postulated differences in the pattern of metastatic spread, represented by the steepness of the slope of the relationship between numbers of tumors present and tumor diameter. The clinical pilot study entailed the treatment of five children with advanced neuroblastoma using a combination of 131I metaiodobenzylguanidine (mIBG) and total body irradiation followed by bone marrow rescue. RESULTS: The theoretical analysis shows that both intrinsic radiosensitivity and pattern of metastatic spread can influence the composition of the ideal optimum combination strategy. High intrinsic radiosensitivity generally favors a high proportion of targeting component in the combination treatment, while a strong tendency to micrometastatic spread favors a major contribution by total body irradiation. The neuroblastoma patients were treated using a combination regimen with an initially low targeting component (2 Gy whole body dose from targeting component plus 12 Gy from total body irradiation). The treatment was tolerable and resulted in remissions in excess of 9 months in each of these advanced neuroblastoma patients. CONCLUSIONS: Radiobiological analysis, which incorporates simple models of metastatic spread, emphasizes the importance of the total body irradiation component in a targeting/total body irradiation combination strategy. However, the analysis favors a larger targeting component than is used in clinical practice at present. A cautious escalation of the 131I mIBG component in the combination treatment of advanced neuroblastoma appears justified.

Child↗
PubMed1995

A stochastic model for multistage tumorigenesis in developing and adult mice.

A stochastic process model for one-, two-, and three-stage malignant transformation has been developed for embryonic and adult mice. The model has been used to study the influence of mutation rate, number of stages required for transformation, and number of stem cells at risk on the kinetics of spontaneous appearance of malignant tumors. As expected, tumors appeared earlier with fewer required mutational stages, higher mutation rate, and greater number of stem cells at risk. However, a notable observation was that tumor latency was more strongly influenced by number of stages and by stem cell number at lower mutation rates than at higher rates. This implies that tumor latency may be a less useful observation when the spontaneous mutation rate is high. In the future, the model will be applied to analysis of tumorigenesis experiments in transgenic mice with p53 genetic abnormalities, subjected to irradiation or chemical tumorigenesis at different stages of development.

Animals↗
PubMed1995

Multi-modality megatherapy with [131I]meta-iodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: feasibility study of a new strategy for advanced neuroblastoma.

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [131I]meta-iodobenzylguanidine ([131I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [131I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

3-Iodobenzylguanidine↗
PubMed1995

Dosimetric considerations in 131I-MIBG therapy for neuroblastoma in children.

Dosimetric calculations have been made for organ doses in patients receiving 131I-MIBG therapy as treatment for neuroblastoma. As well as whole body and liver dose, consideration has been given to dosimetry of organs (lung, urinary bladder) whose tolerance may become treatment limiting when 131I-MIBG is given as part of combined modality therapy. Data from both adults and children receiving radiolabelled MIBG for diagnostic or therapeutic purposes have been compared in constructing dosimetry models for children. A recently published urodynamic model has been used in the estimation of radiation dose to the bladder. The results show that liver and lung may receive doses greater than the average total body dose (0.58 mGy MBq-1 and 0.35 mGy MBq-1, respectively, as compared with 0.25 mGy MBq-1 to the whole body). The organ dose estimates do not differ greatly from previous analyses except in the case of the bladder for which the new modelling studies have resulted in lower dose estimates (0.76 mGy MBq-1 administered, for dose to bladder surface from bladder contents) than in some published series. This may result from differing assumptions regarding parameters such as bladder content and urine flow rate, an enhanced fluid intake being assumed in the present bladder dose estimates. Average doses to the bladder wall from the contents were estimated to be 7.4-11.3% of the surface doses. The urodynamic modelling analysis shows that the bladder could receive a much greater dose (by an order of magnitude) in patients who were inadequately hydrated or had impaired renal function.

3-Iodobenzylguanidine↗
PubMed1995

Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides.

UNLABELLED: Targeted radionuclide therapy is a new form of radiotherapy that differs in some important respects from external beam irradiation. One of the most important differences is due to the finite range of ionizing beta particles emitted as a result of radionuclide disintegration. The effects of particle range have important implications for the curability of tumors. METHODS: We used a mathematical model to examine tumor curability and its relationship to tumor size for 22 beta-emitting radionuclides that may have therapeutic potential. The model assumed a uniform distribution of radionuclide throughout. RESULTS: For targeted radionuclide therapy, the relationship between tumor curability and tumor size is different from that for conventional external beam radiotherapy. With targeted radionuclides, there is an optimal tumor size for cure. Tumors smaller than the optimal size are less vulnerable to irradiation from radionuclides because a substantial proportion of the disintegration energy escapes and is deposited outside the tumor volume. CONCLUSION: We found an optimal tumor size for radiocurability by each of the 22 radionuclides considered. Optimal cure diameters range from less than 1 mm for short-range emitters such as 199Au and 33P to several centimeters for long-range emitters such as 90Y and 188Re. The energy emitted per disintegration may be used to predict optimal cure size for uniform distributions of radionuclide.

Beta Particles↗
PubMed1994

N-myc gene copy number in neuroblastoma cell lines and resistance to experimental treatment.

The N-myc oncogene is amplified in approximately 30% of neuroblastomas. It is well established that cases of neuroblastoma with amplified N-myc have markedly poorer prognosis than those in which N-myc copy number is not elevated. The mechanism for this association is not known but may be related to cellular resistance to radiation or cytotoxic drugs. Seven human neuroblastoma cell lines were used to investigate the relationship between N-myc copy number or expression and sensitivity to ionising radiation and to cisplatin. N-myc copy number was assessed by Southern blotting and hybridisation using the p-Nb1 probe. The signal produced by DNA from the cell lines was compared with that of single copy N-myc from normal human placental DNA. A range of N-myc copy numbers from 1 to 800 was found. Expression levels of N-myc mRNA were compared by "dot blotting" and subsequent hybridisation to the p-Nb1 probe. Radiosensitivity was assessed by surviving fraction at 2 Gy (SF2) following 60Co gamma irradiation. Values ranged from 0.13 to 0.52. Sensitivity to cisplatin was indicated by comparison of isoeffective concentrations (concentration required to produce 1 log cell kill). These ranged from 7.5 to 13 microM. Cisplatin studies showed a correlation between N-myc copy number (though not expression) and resistance to this drug. If this relationship is causal it may explain why treatment fails in those patients with an elevated N-myc copy number. However, no correlation was found between N-myc copy number or expression and sensitivity to radiation. It is possible that N-myc amplification confers resistance to some but not all treatments used in the therapy of neuroblastoma. Further investigations along these lines may lead to the identification of agents which are most appropriate for the treatment of neuroblastoma with amplified N-myc gene.

Blotting, Southern↗
PubMed1994

Prediction of accumulation of 131I-labelled meta-iodobenzylguanidine in neuroblastoma cell lines by means of reverse transcription and polymerase chain reaction.

Radiolabelled meta-iodobenzylguanidine (mIBG) currently provides one of the most promising options for targeted radiotherapy of neuroblastoma. No means currently exists for prediction of mIBG uptake in tumour cells of individual patients other than semiquantitative inferences from diagnostic scanning which depend on the continued existence of a macroscopic tumour mass. A biological rapid assay which could be applied at initial biopsy would be invaluable in selecting patients for therapeutic strategies which incorporate radiolabelled mIBG. We have assessed the expression of the noradrenaline transporter gene in six human neuroblastoma cell lines and in three non-neural crest-derived cell lines using reverse transcription followed by the polymerase chain reaction. Transcription of this gene was observed in five out of six neuroblastoma cell lines but in none of the control cells. A highly significant correlation was established (P < 0.01) between gene expression and active cellular accumulation of mIBG. It is suggested that semiquantitative evaluation of noradrenaline transporter gene transcripts may be predictive of mIBG uptake by tumours in vivo.

3-Iodobenzylguanidine↗
PubMed1994

Modification of meta-iodobenzylguanidine uptake in neuroblastoma cells by elevated temperature.

Successful imaging or treatment of neuroblastoma with 131I-meta-iodobenzylguanidine (131I-mIBG) depends on the selectivity of active (type 1) uptake of mIBG in neuroblastoma cells relative to passive (type 2) uptake present in most normal tissues. This study investigates the effects of moderately elevated temperature (39-41 degrees C) on the cellular uptake of 131I-mIBG in two neuroblastoma cell lines [SK-N-BE(2c) and IMR-32] and in a non-neuronal (ovarian carcinoma) cell line (A2780). In SK-N-BE(2c), a cell line with high active uptake capacity, the specific (type 1) uptake was reduced by 75% (P < 0.001) at 39 degrees C. Both IMR-32 and A2780 have a low capacity for accumulation of mIBG by active uptake. These cell lines demonstrated a statistically significant increase in accumulation at 39 degrees C, mainly as a result of increased non-specific transport. At 41 degrees C uptake of 131I-mIBG was reduced in all cell lines. Thus, the active component of mIBG uptake is more vulnerable to increased temperature than the passive component. It seems probable that moderately increased temperature will have an unfavourable effect on the therapeutic differential for targeted radiotherapy of neuroblastoma using radiolabelled mIBG.

3-Iodobenzylguanidine↗
PubMed1994

Targeting radiation to tumours.

Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Variant forms of this are the binary strategies (neutron capture therapy, photodynamic therapy) in which cell killing by the targeting moiety is dependent on activation by an external radiation beam. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In the future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known.

Boron Neutron Capture Therapy↗
PubMed1993

Radiobiological modeling of combined targeted 131I therapy and total body irradiation for treatment of disseminated tumors of differing radiosensitivity.

PURPOSE: A model is presented for calculating combinations of targeted 131I and total body irradiation, followed by bone marrow rescue, in the treatment of tumors of different radiosensitivity. The model is used to evaluate the role of the total body irradiation component in the optimal combination regime as a function of the radiosensitivity of the tumor cells. METHODS AND MATERIALS: A microdosimetric model was used to calculate absorbed dose in small tumors and micrometastases when uniformly targeted by the radionuclide 131I. Cell kill was calculated from absorbed dose using an extended version of the linear quadratic model. The addition of varying total doses of total body irradiation, assuming 2 Gy fractions, was also calculated using the linear quadratic model. The net cell kill from combined modality (targeted 131I and total body irradiation) was computed for varying proportions of the two components, for a range of tumor sizes, restricting the total radiation dose to within tolerance for a full-course TBI regime (approximately 14 Gy total) in all cases. The calculations were repeated for a range of presumed tumor uptakes of the targeting agent and for a range of tumor radiosensitivities, typical of those reported for tumor cells of differing type in culture. Optimal regimes were identified as those predicted to yield a high probable tumor cure rate (evaluated using a Poisson statistical model) for all tumor sizes. RESULTS: The analysis supports earlier model studies which predicted that systemic combination treatment with targeted 131I and total body irradiation would be superior to either component used alone. The intrinsic tumor radiosensitivity is found to be a factor which influences the optimal combination of the 131I and external beam total body irradiation components. The total body irradiation component is greater in optimal regimes treating radio-resistant than radiosensitive tumors. However, an obligatory total body irradiation component is also predicted for more radiosensitive tumors; the analysis suggests that the total body irradiation component should in no circumstances be less than 2 x 2 Gy, whilst practical arguments exist in favor of higher doses. CONCLUSION: Total body irradiation is an obligatory component for effective systemic treatment of disseminated malignant tumors to which 131I can be selectively targeted. Clinical studies applying this strategy to the treatment of neuroblastoma by 131I targeted by meta-iodo-benguanidine (mIBG), total body irradiation and bone marrow rescue are now in progress.

Dose-Response Relationship, Radiation↗
PubMed1993

The effect of differing radiotherapeutic schedules on the response of glottic carcinoma of the larynx.

Laryngeal tumours, especially T1N0M0 and T2N0M0 lesions, are readily controlled by radiotherapy. Studies have shown that control varies with the dose of radiotherapy delivered to the tumour. Other factors, including the dose per fraction and the time over which the treatment schedule is delivered are also important. The varying biological effectiveness of a number of different dose fraction time schedules used in the management of laryngeal tumours of different stages are considered, the end points being tumour control and associated morbidity. Special attention has been given to the length of time over which the schedule is delivered. Of the schedules examined the results would suggest that a dose of 60 Gy given in 25 fractions over a period of 35 days is the best of the six schedules studied for T1, T2, T3 and T4 lesions with minimal associated morbidity. It is possible, however, that the poor results shown on the Kaplan-Meier curves for patients treated with the schedule of 60 Gy in 30 fractions over a period of 42 days could be due to geographical misses of the tumours as 56% were treated without a beam directed shell. The poor result obtained when patients were treated with the schedule of 60 Gy given in 30 fractions over 49+ days may be due to tumour repopulation occurring during the rest period though the possibility of geographical misses may contribute to the poor tumour control results. Mathematical modelling using linear quadratic analysis suggests that the shorter the period of time over which the treatment is given the better chance of achieving tumour control irrespective of the stage of the disease. These models were developed for patients treated with a beam directed shell thus excluding those patients who are most likely to be at risk from a geographic miss of the tumour. Linear quadratic analysis of the treatment data suggests that the ratio alpha/beta for tumour cells is estimated in the region of 13 Gy. For T1 lesions the tumour doubling time is in the order of 6 days, with longer doubling times for the more advanced stages. The analysis provides some support for investigative use of accelerated treatment schedules. This analysis also shows the importance of using beam directed shells when treating small fields especially in the head and neck region.

Adult↗
PubMed1993

Kinetic considerations in the choice of treatment schedules for neuraxis radiotherapy.

Neuraxis radiotherapy of radiosensitive tumours such as medulloblastoma is usually carried out using conventionally sized fractions and a shrinking field technique. Plowman and Doughty (Br. J. Radiol., 64 (1991) 603-607) have proposed a partial transmission block (PTB) technique which entails the use of small daily doses over a conventional time period. Radiobiological analysis suggests that, although the PTB technique may be adequate for slowly growing tumours, therapeutic efficacy is likely to be compromised where the tumour doubling time is short. Accelerated hyperfractionation (twice daily fractions) provides a possible alternative to both conventional scheduling and the PTB technique. Direct measurement of the kinetics of tumour cells in CSF, where possible, may provide useful guidance in the choice of regimes.

Cell Survival↗
PubMed1992

131I-meta-iodobenzylguanidine therapy in neuroblastoma spheroids of different sizes.

Mathematical models have predicted that targeted radiotherapy of neuroblastoma with metaiodobenzylguanidine (mIBG) is less likely to cure small rather than large micrometastases if 131I is the conjugated radionuclide. This study uses multicellular tumour spheroids as an in vitro model to test the hypothesis that smaller tumours of sub-millimetre dimensions are relatively resistant to 131I-mIBG. Spheroids of the human neuroblastoma cell line SK-N-BE(2c), either 250 microns or 400 microns diameter, were incubated with 131I-mIBG at concentrations of up to 6.0 MBq ml-1. Using both regrowth delay and spheroid 'cure' as endpoints, the greater vulnerability of larger spheroids was confirmed. From this in vitro result we conclude that when used in vivo 131I-mIBG may spare smaller micrometastases. Therefore, either a radionuclide such as 211At which emits a shorter path length radiation should be conjugated to mIBG, or targeted radiotherapy should be combined with a treatment such as total body irradiation, the efficacy of which is not reduced in smaller tumours.

3-Iodobenzylguanidine↗