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T E Wheldon

Publications and source records attributed to T E Wheldon.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Alternative models for early onset of childhood leukaemia.

This paper considers theoretical models for early-onset childhood leukaemia. The major focus of attention is the two-hit mutational model. A simple mathematical representation is used to explore mechanisms which might lead to onset of leukaemia at an unusually early age. Two such mechanisms are considered. The first of these, a germinal or very early embryonic first mutation is shown to imply that multiple independent leukaemic clones are likely to arise sequentially in very young patients. Clonal multiplicity could underlie the poor prognosis which has been associated with early onset childhood acute lymphoblastic leukaemia. It implies that curative therapy might require intensive treatment followed by bone marrow rescue to ensure eradication of all single-hit predisposed target cells. The prediction of multiple leukaemic clones might be tested in female patients by means of X-linked restriction fragment length polymorphisms and in patients with B-lineage neoplasms by determination of immunoglobin gene rearrangements. A second mechanism for early onset leukaemogenesis is the occurrence of a high cellular mutation rate in some patients. This is shown to result in leukaemia at significantly earlier age if the mutation rate is sufficiently high to influence target cell loss rate. This mechanism would enable more rapid clonal evolution of leukaemic cells and the early emergence of drug resistant variants. The prediction might be tested experimentally by sequential observation of genetic markers (e.g. Karyotypes, DNA fingerprint patterns) and the rate of emergence of drug resistant phenotypes. Other models, considered more briefly, include one-hit mutational 'dominants' in the developing embryo and faster growth kinetics in neoplasms of younger patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Division↗
PubMed1991

The curability of tumours of differing size by targeted radiotherapy using 131I or 90Y.

A mathematical model has been used to investigate the relationship of curability to tumour size and cell number for spherical tumours treated with targeted 131I or 90Y, assuming uniform uptake of radionuclide throughout the tumour. The analysis shows that, for any given cumulated activity per unit mass of tumour, cure probability is greatest for tumours whose diameter is close to an optimum value which depends on the path length of the emitted beta-particle. Smaller tumours are less curable because of inefficient absorption of radiation energy, and larger tumours are less curable because of greater clonogenic cell number. The lesser curability of very small tumours is a feature of targeted radiotherapy using long-range beta-emitters which does not occur with external beam irradiation. The predicted inefficiency of sterilisation of microscopic tumours poses a problem for targeted radiotherapy which is analogous to "geographic miss" in conventional radiotherapy. The implication is that small micro-metastases could escape sterilisation by radionuclides administered at activity levels sufficient to eradicate larger tumours. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated malignancy when multiple tumours of differing size, including micrometastases, may be present. The analysis implies that an advantage might result from the use of a panel of several radionuclides (including short-range emitters) or from combining targeted radiotherapy using long-range beta-emitters with external beam irradiation or some other modality to which microscopic tumours are preferentially vulnerable.

Beta Particles↗
PubMed1991

Implications of the uptake of 131I-radiolabelled meta-iodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma.

Selective uptake of radiolabelled meta-iodobenzylguanidine (mIBG) in neuroblastoma provides a possible approach to biologically targeted radiotherapy of this disease. A mathematical model was used to predict absorbed doses to tumours of varying size from therapeutic 131I-mIBG, based on measurements of 125I-mIBG uptake in surgically excised tumours from six patients. Two size categories of tumour target were considered: bulk tumour and microscopic disease. The predicted absorbed doses were compared with doses calculated to achieve a 50% probability of tumour cure. The analysis shows that the probability of tumour cure depends strongly on mIBG uptake, effective half-life of mIBG in tumour and tumour diameter. Small microtumours may be relatively resistant to mIBG treatment owing to the limited absorption of 131I beta-energy. The product of patient mass and percentage uptake per unit mass of tumour may be a useful indicator of therapeutic outcome when targeted radiotherapy is used for the treatment of paediatric tumours.

3-Iodobenzylguanidine↗
PubMed1990

Tumor spheroid model for the biologically targeted radiotherapy of neuroblastoma micrometastases.

Neuroblastoma is a pediatric malignancy with a poor prognosis at least partly attributable to an early pattern of dissemination. New approaches to treatment of micrometastases include targeted radiotherapy using radiolabeled antibodies or molecules which are taken up preferentially by tumor cells. Multicellular tumor spheroids (MTS) resemble micrometastases during the avascular phase of their development. A human neuroblastoma cell line (NBl-G) was grown as MTS and incubated briefly with a radiolabeled monoclonal antibody (131I-UJ13A) directed against neuroectodermal antigens. Spheroid response was evaluated in terms of regrowth delay or proportion sterilized. A dose-response relationship was demonstrated in terms of 131I activity or duration of incubation. Control experiments using unlabeled UJ13A, radiolabeled nonspecific antibody (T2.10), radiolabeled human serum albumin, and radiolabeled sodium iodide showed these to be relatively ineffective compared to 131I-UJ13A. The cell line NBl-G grown as MTS has also been found to preferentially accumulate the radiolabeled catecholamine precursor molecule m-[131I]iodobenzylguanidine compared to cell lines derived from other tumor types. NBl-G cells grown as MTS provide a promising laboratory model for targeted radiotherapy of neuroblastoma micrometastases using radiolabeled antibodies or m-iodobenzylguanidine.

Antibodies, Monoclonal↗
PubMed1990

The radiobiology of targeted radiotherapy.

Targeted radiotherapy consists of biologically selective irradiation of malignant cells by means of radionuclides attached to tumour-seeking molecules. A variety of clinical strategies for targeted radiotherapy may be used, for which different normal tissues will be critical. A large number of radionuclides exist, emitting nuclear particles with a range of path lengths from nanometres to millimetres. An important feature of normal-tissue radiobiology is the dose-rate effect, which is especially marked for late-responding tissues. Radiobiological calculations imply that tolerance dose for targeted radiotherapy using low-LET emitters will depend strongly on the effective half-life of the radionuclide, which will be affected by pharmacokinetics and may vary between patients. Some strategies designed to improve the therapeutic radio (e.g. accelerated clearance of radionuclide) may have modulating effects on the tolerance dose. Tumour response will be governed by the 'four Rs' (repair, repopulation, reoxygenation, redistribution) as well as by mechanisms peculiar to targeted radiotherapy. Analysis based on the extended linear quadratic model predicts that dose-rate effects will be of major importance for only a minority of tumours. Most of the radiation dose to tumour will usually be delivered over a time-scale of a few days. This might give insufficient time for tumour reoxygenation, making the use of hypoxic sensitizers appropriate. A special feature of targeted radiotherapy is the complex relationship between tumour curability and tumour size for different radionuclides. For long-range beta-emitters, microscopic tumours may be operationally resistant because of inefficient absorption of radionuclide disintegration energy in small volumes. Short-range emitters will be more efficient in sterilization of micrometastases but sterilization of larger tumours may require an unattainable degree of homogeneity of radionuclide distribution. Optimal use of targeted radiotherapy may require it to be combined with external-beam irradiation or chemotherapy. Experimental studies will be necessary to investigate those features of targeted radiotherapy which differ from external-beam irradiation. Future directions may include targeted radiotherapy of minimal numbers of tumour cells detected by use of molecular probes. Such applications call for use of short-range alpha-emitters and Auger emitters whose radiobiology will become increasingly important.

3-Iodobenzylguanidine↗
PubMed1990

Radiobiological rationale for compensation for gaps in radiotherapy regimens by post-gap acceleration of fractionation.

It is now recognized that clonogenic tumour cells may repopulate vigorously during radiotherapy. Gaps in treatment schedules which lead to prolongation of overall treatment time may therefore cause sparing of tumour. Acute-responding normal tissues will also be spared if repopulation by surviving stem cells takes place. However, it is unlikely that stem cells in late-responding normal tissues repopulate significantly over the time-scale of a conventional treatment regime; these tissues will therefore experience little or no sparing as a result of a gap. This poses a dilemma since tumour cell repopulation implies that an increased therapeutic effect in the post-gap phase of treatment may be necessary to compensate for any prolongation of treatment time, but it is difficult to achieve increased tumour effect without also increasing damage to late-responding normal tissues. Neither increased total dose nor increased fraction size is able to achieve this. A possible solution is provided if total treatment time can be held constant, with unchanged total dose and fraction size, by use of twice-daily conventionally sized dose fractions administered after the gap. Provided the twice-daily fractions are sufficiently spaced (not less than 6-8 h apart), the result will be to offset repopulation in tumour and acute-responding normal tissues without additional impairment of late-responding normal tissues. The feasibility of the approach depends on being able to complete treatment by the time originally intended; it is therefore more readily applicable to gaps occurring early rather than late in a treatment schedule. The strategy should be especially advantageous for tumours with rapid repopulative potential in sites where risk of damage to late-responding normal tissues imposes limitation of dose.

Humans↗
PubMed1989

The relative effectiveness of analogues of cisplatin in the experimental chemotherapy of human non-small-cell lung cancer and neuroblastoma grown as multicellular spheroids.

We compared cisplatin (cis-DDP) and two of its analogues, carboplatin (JM8, CBDCA) and iproplatin (JM9, CHIP) for their ability to retard the growth of multicellular tumour spheroids. The spheroids were derived from two human tumours, a neuroblastoma and a non-small-cell lung cancer. To produce a given level of regrowth delay in lung cancer spheroids, carboplatin and iproplatin were required at concentrations approximately 10 times that of cis-DDP. In the neuroblastoma spheroid experiments, iproplatin and cis-DDP produced the same level of regrowth delay when iproplatin was present at a concentration greater than 10 times that of cis-DDP. Carboplatin also required much higher concentrations than cis-DDP to produce equivalent regrowth delay in neuroblastoma. The dose-response curve produced by carboplatin on neuroblastoma spheroids displayed a pronounced shoulder in the low-dose region; this phenomenon was not seen with cis-DDP. These findings may have implications for the clinical use of these drugs and in particular would support a role for carboplatin in the treatment of lung cancer, since total free-drug exposure of patients to carboplatin may be up to 16-fold greater than with cis-DDP. However, one must be cautious about generalizing on the basis of results from only two cell lines as well as applying in vitro data to clinical situations.

Carboplatin↗
PubMed1989

Etoposide (VP-16) uptake by tumour spheroids and activity in the presence of Brij 30, formulation additives and sodium salicylate.

A number of additives typically used in the formulation of poorly soluble drugs can be shown to influence drug transport across various physiological barriers. Multicellular spheroids from a human neuroblastoma cell line (NB1-G) were used to investigate the effect of etoposide in solution, as its commercial formulation, Vepesid, in the presence of a nonionic surfactant, Brij 30, and a hydrotropic agent, sodium salicylate. Enhanced growth delay, apparently related to increased drug uptake, was observed both with the Vepesid and the sodium salicylate formulations. Brij 30, however, showed no enhancement of growth delay or drug uptake at a concentration at which it was not in itself cytotoxic. Significant morphological changes in the spheroid were observed at higher concentrations of additives, particularly with Brij 30, emphasizing the fact that many formulation additives cannot be used with impunity in tissue culture systems. The enhanced uptake of drug into tumour cells and potential synergy between additive and drug is worthy of further investigation.

Adjuvants, Pharmaceutic↗
PubMed1988

Strategies for systemic radiotherapy of micrometastases using antibody-targeted 131I.

A simple analysis is developed to evaluate the likely effectiveness of treatment of micrometastases by antibody-targeted 131I. Account is taken of the low levels of tumour uptake of antibody-conjugated 131I presently achievable and of the "energy wastage" in targeting microscopic tumours with a radionuclide whose disintegration energy is widely dissipated. The analysis shows that only modest doses can be delivered to micrometastases when total body dose is restricted to levels which allow recovery of bone marrow. Much higher doses could be delivered to micrometastases when bone marrow rescue is used. A rationale is presented for targeted systemic radiotherapy used in combination with external beam total body irradiation (TBI) and bone marrow rescue. This has some practical advantages. The effect of the targeted component is to impose a biological non-uniformity on the total body dose distribution with regions of high tumour cell density receiving higher doses. Where targeting results in high doses to particular normal organs (e.g. liver, kidney) the total dose to these organs could be kept within tolerable limits by appropriate shielding of the external beam radiation component of the treatment. Greater levels of tumour cell kill should be achievable by the combination regime without any increase in normal tissue damage over that inflicted by conventional TBI. The predicted superiority of the combination regime is especially marked for tumours just below the threshold for detectability (e.g. approximately 1 mm-1 cm diameter). This approach has the advantage that targeted radiotherapy provides only a proportion of the total body dose, most of which is given by a familiar technique. The proportion of dose given by the targeted component could be increased as experience is gained. The predicted superiority of the combination strategy should be experimentally testable using laboratory animals. Clinical applications should be cautiously approached, with due regard to the limitations of the theoretical analysis.

Antibodies, Monoclonal↗
PubMed1988

A tumour spheroid model for antibody-targeted therapy of micrometastases.

Human neuroblastoma cells grown as tumour spheroids were briefly incubated with a conjugate of 131I and an anti-human neuroectodermal monoclonal antibody UJ13A. Unbound 131I was removed by washing and the spheroids observed in culture conditions for up to 4 weeks. Spheroid response to irradiation was evaluated as time to reach 10x treatment volume and proportion of spheroids sterilised. Spheroid growth was found to be affected by both the activity of 131I-UJ13A and the duration of the incubation. Na[131I], 131I-HSA, 131I labelled non-specific antibody and unlabelled antibody were found to be relatively ineffective compared to 131I-UJ13A. The tumour spheroid model has applications in the evaluation of antibodies or antibody fragments and different radionuclides which may be considered for radioimmunotherapy of micrometastases.

Antibodies, Monoclonal↗
PubMed1988

Cytotoxic drug penetration studies in multicellular tumour spheroids.

1. The three-dimensional structure of human lung tumour spheroids conferred a degree of resistance to the anthracyclines adriamycin, 4'-deoxydoxorubicin, daunomycin and daunomycin-low density lipoprotein complex in comparison with cells grown as a monolayer, as assessed by delayed growth and clonogenic cell survival. 2. 4'-Deoxydoxorubicin induced a longer growth delay and greater clonogenic cell kill than adriamycin in spheroids, although it was no more cytotoxic in monolayer. 3. Fluorescent microscopy demonstrated that the more lipophilic analogues partitioned into the spheroid more rapidly and to a greater degree than adriamycin. 4. The spheroid model demonstrated that penetration is an important aspect of resistance to anthracycline drugs, and this approach may represent a better in vitro system for testing lipophilic analogues of cytotoxic drugs.

Antibiotics, Antineoplastic↗