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T E Wheldon

Publications and source records attributed to T E Wheldon.

At least 37 records · Page 2Linked to original sources
PubMed1997

The radiobiological basis of total body irradiation.

Total body irradiation (TBI) is an all-pervasive systemic treatment modality which is well suited to the sterilization of small numbers of widely dispersed radiosensitive cells. This makes it attractive for the treatment of leukaemia or lymphoma in remission. It is unlikely that hypoxia or repopulation will be a problem in TBI treatment of leukaemia, and clonal resistance to radiation occurs less readily than to drugs. Leukaemic cells are often radiosensitive with poor repair capacities but considerable variation is seen in laboratory studies and leukaemias may be highly individual. It is possible that programmed cell death (apoptosis) contributes to leukaemic cell killing and variability of apoptosis may give rise to biological individuality. Molecular methodologies may now be used to monitor leukaemic cell populations and may enable semi-quantitative predictive assays of radiosensitivity. When the malignant cell population is not uniformly distributed throughout the body, as in lymphoma, non-uniform TBI is appropriate, e.g. by addition of local boosts or by the combination of TBI with radiolabelled antibody treatment. Major side-effects mostly relate to critical organs with late-responding characteristics (low alpha/beta ratio, high sensitivity to fraction size or dose rate). The radiobiological basis of developmental effects in children is not well understood. In future, improved selectivity of TBI may come from molecular biological strategies to sensitize malignant cells and to protect normal tissues.

Apoptosis↗
PubMed1996

A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy.

There is much evidence for the detrimental effect on tumour control of missed treatment days during radiotherapy, amounting for example to approximately a 1.6% absolute decrease in local control probability per day of treatment prolongation in the case of head and neck squamous cell cancer. Various methods to compensate for missed treatment days are compared quantitatively in this article, using the linear-quadratic formalism. The overall time and fraction size can be maintained by either treating on weekend days (the preferred way (Method 1a), although with unsocial hours and at extra cost) or using two fractions per day to "catch up' (Method 1b). The latter might incur a small loss of tolerance regarding late reactions, when intervals of 6-8 h are used rather than 24 h, and there may be logistical/scheduling difficulties with larger numbers of patients in some centres when using this method. A second type of strategy retains overall treatment time, and also one fraction per day, but the size of the dose per fraction is increased. For example, this may be done for the same number of "post-gap' days as gap days (Method 2). However, with this method, calculated isoeffect doses regarding late reactions indicate a probable decrease in tumour control rate (Method 2a). Otherwise, isoeffective doses regarding tumour control result in an increase in late reactions (Method 2b). In addition, this method is unsuitable for short regimens already using high doses per fraction. To reduce this problem, overall treatment time can also be retained by using fewer fractions, all of greater size in the case of planned gaps (statutory holidays), or larger remaining fractions after unplanned gaps (Method 2c). The problem also with this method is that equivalence for tumour control gives an increase in late reactions. The least satisfactory strategy (Method 3) is to accept the protraction caused by the missed treatment days, and give either the same prescribed number of (slightly larger) fractions or the planned treatment followed by one (or more) extra fraction to compensate for the gap. This would retain the expected local control rate, but there would be an increase in late reactions. An example of this, using average parameter values, is that a 3-day gap (necessitating four extra days to complete treatment with one fraction of 2.4 Gy) might maintain a 70% local control rate for glottic carcinoma, but severe reactions might rise from 1% to 4% and minor/moderate reactions from 37% to 50%. In this example, the inclusion of an extra weekend would increase the required extra dose and hence may further increase the morbidity rates. A final point is that the effect of treatment interruptions for an individual patient is expected to be greater than that for a group of patients because of interpatient heterogeneity tending to flatten dose-response curves. Calculations show that the above value of 1.6% loss of local control per day for a group of patients may reflect values for individual patients that range around a median value of as much as 5% per day, so stressing further the importance of gaps in treatment. It is concluded that, wherever possible, treatment days should not be missed. If they are missed, it is important to compensate for them, preferably by one of the first of the above methods (1a or 1b), in order to keep as close as possible to the original/standard prescription in terms of total dose, dose per fraction and overall time.

Brachytherapy↗
PubMed1996

Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party.

Radiation myelopathy (RM) is an uncommon but serious late effect of thoracic radiotherapy (RT), which oncologists try to avoid by careful planning and dose selection. Five patients with RM are described from among 1048 with inoperable non-small cell lung cancer treated with palliative RT in three randomized trials conducted by the Medical Research Council Lung Cancer Working Party. Seven RT regimens were used in these trials: 10 Gy in a single fraction on one day (10/1/1) (114 patients), 17/2/8 (524 patients), 27/6/11 (47 patients), 30/6/11 (36 patients), 30/10/12 (88 patients), 36/12/16 (86 patients) and 39/13/17 (153 patients). Of the five instances of RM, three occurred in the 524 patients treated with 17 Gy in two fractions, and two in the 153 treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17 Gy group, 2.5% for the 39 Gy group, and 0% for the remainder, but the annual risks had wide 95% confidence intervals, indicating that the distribution of episodes among the seven regimens could have been random. Nevertheless, calculation of cord doses in terms of the total doses that would have an equivalent biological effect if given in 2 Gy fractions (LQED2 values) from our data for different values of the ratio of the linear quadratic parameters of the cell survival curve (alpha/beta), suggest that the best estimate of alpha/beta is less than 3 Gy, and possibly close to 2 Gy. This emphasizes the sensitivity of human spinal cord to changes in fraction size. We recommend that, when the computed LQED2 for a schedule of treatment that includes the thoracic spinal cord (assuming alpha/beta = 2 for cord) exceeds 48 Gy, oncologists should consider reducing the dose to the cord.

Aged↗
PubMed1996

Targeted radiotherapy using Auger electron emitters.

Auger-emitting radionuclides have potential for the therapy of cancer due to their high level of cytotoxicity and short-range biological effectiveness. Biological effects are critically dependent on the sub-cellular (and sub-nuclear) localization of Auger emitters. Mathematical modelling studies suggest that there are theoretical advantages in the use of radionuclides with short half-lives (such as 123I) in preference to those (such as 125I) with long half-lives. In addition, heterogeneity of radionuclide uptake is predicted to be a serious limitation on the ultimate therapeutic effect of targeted Auger therapy. Possible methods of targeting include the use of analogues of DNA precursors such as iodo-deoxyuridine and molecules which bind DNA such as steroid hormones or growth factors. A longer term possibility may be the use of molecules such as oligonucleotides which can discriminate at the level of DNA sequence. It seems likely that the optimal clinical role of targeted Auger therapy will be as one component of a multi-modality therapeutic strategy for the treatment of selected malignant diseases.

Estrogens↗
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↗