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J Denekamp

Publications and source records attributed to J Denekamp.

At least 37 records · Page 2Linked to original sources
PubMed1999

Inducible repair and the two forms of tumour hypoxia--time for a paradigm shift.

Clinical experience shows that there is a therapeutic window between 60 and 70 Gy where many tumours are eradicated, but the function of the adjacent normal tissues is preserved. This implies much more cell kill in the tumour than is acceptable in the normal tissue. An SF2 of 0.5 or lower is needed to account for the eradication of all tumour cells, while an SF2 of 0.8 or higher is needed to explain why these doses are tolerated by normal tissues. No such systematic difference is known between the intrinsic sensitivity of well-oxygenated normal and tumour cells. The presence of radioresistant hypoxic cells in tumours makes it even more difficult to understand the clinical success. However, there is experimental evidence that starved cells lose their repair competence as a result of the depletion of cellular energy charge. MRS studies have shown that low ATP levels are a characteristic feature of solid tumours in rodents and man. In this paper we incorporate the concept of repair incompetence in starving, chronically hypoxic cells. The increased sensitivity of such cells has been derived from an analysis of mammalian cell lines showing inducible repair. It is proportional to the SF2 and highest in resistant cells. The distinction between acutely hypoxic radioresistant cells and chronically hypoxic radiosensitive cells provides the key to the realistic modelling of successful radiotherapy. It also opens new conceptual approaches to radiotherapy. We conclude that it is essential to distinguish between these two kinds of hypoxic cells in predictive assays and models.

Cell Hypoxia↗
PubMed1999

Accelerated radiotherapy, carbogen, and nicotinamide in glioblastoma multiforme: report of European Organization for Research and Treatment of Cancer trial 22933.

PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.

Administration, Inhalation↗
PubMed1998

Hyperfractionation as an effective way of overcoming radioresistance.

PURPOSE: To model the influence of hypoxic radioprotection in fractionated treatments over a range of fraction sizes. To determine whether there is a "therapeutic window" of dose per fraction where hypoxic radioresistance could be reduced, and if so, where it occurs in different cell lines. MATERIALS AND METHODS: A mathematical model has been used to simulate the response of cells to low doses of radiation, in the region of clinical interest. We have used the inducible repair variant of the linear quadratic (LQ) equation, with a hypersensitive region (alphaS) at low doses that gradually transforms to the accepted "resistance" in the shoulder region (alphaR). It contains two new parameters, the ratio alphaS/alphaR, and D(C). We have accepted that the "induction dose" D(C) is modified by anoxia to the same extent as the other parameters. We have initially modeled using theoretical parameters and then checked the conclusions with 14 sets of published experimental data for cell lines investigated for inducible repair. RESULTS: We have computed the clinical hypoxic protection (OER') as a function of dose per fraction in simulations of clinical fractionated schedules. We have identified a therapeutic window in terms of dose per fraction at about 0.5 Gy, where the OER' is minimized, regardless of the precise cell survival curve parameters. The minimum OER' varies from one cell line to another, falling to about 1.0 if alphaS/alphaR = 6-10 and even far below 1.0 if alphaS/alphaR > or = 20. DISCUSSION: Hyperfractionation using 0.5 Gy fractions may therefore be more effective than oxygen mimetic chemical sensitizers, since it could even make some tumor cells more sensitive than oxic normal tissues. The tumor lines that benefit most from this type of sensitization are those with the highest intrinsic oxic radioresistance, i.e. those with high SF2 values.

Cell Hypoxia↗
PubMed1998

Vasculature and microenvironmental gradients: the missing links in novel approaches to cancer therapy?

This paper illustrates how the concept of the malignant cell per se as the prime and only target in cancer therapy may be erroneous. The micro-vasculature evoked to satisfy nutritional requirements of solid tumors, and the inadequacy of this nutrition for all tumor cells, provide novel targeting concepts. The vascular architecture and the microenvironmental gradients (VAMP) will differ from one tumor to another and may determine whether current therapies succeed or fail. Many agents have a different toxicity or mode of action at the pathophysiological oxygen tensions that prevail in solid tumors. This warrants more attention. The hypoxic cell or the immature proliferating endothelial cell may provide tumor specificity that is more general than, and greater than, that conferred by the process of malignant transformation. The poor vasculature of solid tumors is often regarded as a problem by the oncologist. It limits the access of cytotoxic drugs, monoclonal antibodies, cytokines, etc. It also leads to hypoxic radioresistance because of diffusion limited chronic hypoxia and perfusion limited intermittent hypoxia, resulting from transient vessel closure. However, it can also be seen as a potential target, since prolonged vessel occlusion can lead to an avalanche of cell death. Strategies to prevent further expansion of the vascular network (anti-angiogenesis) should stabilize tumors and prevent further growth. Vascular targeting, aiming to damage the microvascular function and cause occlusion, can lead to extensive cell death. The target may relate to the excessive proliferation of endothelial cells in tumors or to abnormal functional aspects, such as altered cell shape (influencing permeability) adhesiveness to leukocytes or steps in the coagulation cascade. These microvascular features and microenvironmental gradients, and the phenotypic consequences of them, have been relatively neglected. The altered milieu and inadequate neovasculature is a common feature of all types of solid tumor, whereas the genetic changes that can give rise to a malignancy are very variable, from tumor site to site and even within a site from individual to individual. It seems, therefore, that therapies that could be of widespread general applicability might more easily be found from the micro-environmental or anti-vascular approaches than from gene therapy targeted at specific oncogenes. This approach will require cross fertilisation between scientists from quite disparate backgrounds, whose paths seldom cross, and who may not read, or even scan, each other's literature. If the endothelium or the low oxygen tension in subsets of tumor cells are the key to successful cancer treatment in mice, there are considerable implications for screening methods in vitro and for predictive and prognostic tests made on homogenized tumor samples.

Cell Hypoxia↗
PubMed1998

New insights into factors influencing the clinically relevant oxygen enhancement ratio.

BACKGROUND AND PURPOSE: This paper deals with the variations in the oxygen enhancement ratios that could be observed (OER') when comparing oxic and hypoxic cells in different types of fractionated experiments as a consequence of the non-linearity of the underlying cell survival curves. Calculations have been made of the OER' that would be obtained for fractionated irradiations with a series of small doses to allow the comparison of isoeffective doses in oxic and hypoxic conditions. Two styles of fractionated experiment were modelled. In one, the dose per fraction was kept constant in the oxic and hypoxic arms of the experiment, necessitating more fractions in hypoxia to achieve the same level of cell kill. In the other the number of fractions was kept constant and the fraction size was varied to obtain equal levels of damage. The first is the relevant design for the clinic, whereas the second is the design most commonly used in animal studies. MATERIALS AND METHODS: Three models of the survival curve were used to simulate the response of cells to radiation injury, all based on the linear quadratic model, but with various added assumptions. A simple classical LQ model is compared with two models in which the concept of inducible repair is added. In one of these the induction dose for 'switching on' the more resistant response is assumed to be increased in hypoxia and in the other it is assumed to be independent of the oxygen tension. RESULTS: These calculations show a clear and previously unsuspected dependence of the measured OER' on the design of the fractionated experiment. The values obtained in the clinical and animal types of study differ considerably with all three models. The direction and magnitude of that difference depends critically on the assumptions about the fine structure of the survival curve shape. The authors suggest that the inducible repair version with an oxygen-dependent induction dose is probably the most relevant model. Using this, the measured OER' is reduced at doses around 2 Gy for the clinically relevant design of constant sized fractions to the oxic and hypoxic cells. It may even, in certain model assumptions, fall below unity resulting in an increased sensitivity, not resistance, from the hypoxia. CONCLUSIONS: These calculations indicate the urgent need for more knowledge about the fine structure of the low dose region of the survival curves for human tumour cells and especially for comparisons in the presence and absence of oxygen. The extent of the hypersensitivity at very low doses, the trigger dose needed to induce the repair and its oxygen modification may be dominant factors in determining the response of tumour cells to clinically relevant fractionation schedules.

Animals↗
PubMed1998

Factors influencing the estimates of proliferative labelling indices in rectal cancer.

PURPOSE: A detailed analysis was undertaken of some of the factors influencing the estimate of the labelling index (LI). MATERIALS AND METHODS: Thirty-three human rectal carcinomas were studied for their proliferative activity as measured by the fraction of cells labelled with a single injection of IdUrd 1-8 h before surgical resection. Adjacent specimens were stained both for histological examination and for flow cytometry (FCM) assessment of labelled nuclei. RESULTS: Two major differences were found. The superficial parts of each tumour almost always had significantly higher LI values than the deep part (34 versus 21%), yielding an average LI of 27%. The flow cytometry average value was much lower (17%). This was partly due to the influence of diploid tumours. There was a marked heterogeneity in the values, both within tumours, between tumours and between techniques. The average LI for the whole group differs by a factor of three, depending on the method of assessment. CONCLUSIONS: All these values indicate a varying but rapid proliferative turnover of cells, surprisingly being more marked in the superficial region, i.e. the opposite from the proliferation pattern of the normal rectal mucosa. A biopsy, if taken from the superficial part of the tumour, would therefore be biased toward higher values. This has implications for biopsy sampling for cell kinetic analysis. Histological assessment avoids the contaminating effect of stromal cells, allows architectural arrangements to be detected and is presumably a more realistic representation of proliferative activity.

Cell Division↗
PubMed1998

Pharmacokinetics of nicotinamide in cancer patients treated with accelerated radiotherapy: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.

BACKGROUND: The EORTC has initiated studies to combine nicotinamide with carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment protraction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained. AIM: Full pharmacokinetic profiles of nicotinamide concentrations in plasma were analyzed repeatedly in 15 patients to determine the inter- and intra-patient variability in peak plasma concentrations and the optimum times for administering nicotinamide as a radiosensitizer. METHODS: Nicotinamide (Nicobion) was administered in tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose was given regardless of body weight after an overnight fast and at least 30 min before breakfast. In 15 patients, blood samples were taken prior to and 1, 2, 4, 6, 8, 12 and 24 h after administration of the drug. This full profile was determined on two to four occasions for the head and neck cancer patients and on two occasions for the lung cancer patients. For each profile, the maximum concentration of nicotinamide (Cmax), time to peak plasma concentration (Tmax), elimination half-lives (t1/2) and area under the curve (AUC) were determined. Compliance was recorded and nausea and vomiting were graded on a 0-3 scale. Complete profiles of the five major metabolites were also obtained. RESULTS: In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml with a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, but at this time 92% of the profiles had already exceeded the target concentration of 700 nmol/ml, the level required in the mouse for tumour radiosensitization. The median t1/2 for all 15 cases was 9.3 h, with minimum and maximum values of 4.2 and 26.8 h. The highest concentrations of nicotinamide metabolites were found to be the N-oxide, 2-pyridone and 1-methylnicotinamide. The toxicity (nausea and vomiting) was scored and found not to be correlated with any of the pharmacokinetic parameters. CONCLUSIONS: The plasma concentrations considered necessary to radiosensitize can easily be exceeded with a dose of 6 g taken as 12 x 500 mg in tablet form; 700 nmol/ml was achieved in all patients and apparently would have been achieved in most even with a considerable reduction in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles.

Administration, Oral↗
PubMed1997

Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study.

BACKGROUND AND PURPOSE: ARCON (Accelerated Radiotherapy, CarbOgen, Nicotinamide) achieves a large therapeutic gain in rodents. A phase I/II study was therefore undertaken to determine its feasibility in patients with locally advanced head and neck cancer. MATERIALS AND METHODS: The accelerated regime CHART was used in 35 patients given carbogen and/or nicotinamide with 11 small volume fractions. Eight patients received carbogen, 12 received nicotinamide and 15 were treated with ARCON. Treatment compliance, side-effects and acute mucositis were monitored in all cases. RESULTS: All patients underwent CHART as intended. In the 23 patients receiving carbogen, two failed to complete treatment. Compliance with nicotinamide was much lower. Out of 25 patients, only 52% received 10-11 doses of the 80 mg/kg/day of the drug. The most common side-effect was nausea and vomiting, which responded to standard anti-emetics in almost half of the patients. Historical comparisons with the CHART head and neck trials indicate that there was no increase in the severity of acute mucositis in any of these patients. Although the observation period is not sufficiently long to be definitive (median 20 months) there is no evidence of an increase in late normal tissue reactions. CONCLUSIONS: ARCON using CHART as the radiotherapy protocol is feasible in patients with advanced head and neck cancer. However, we are concerned about the low compliance rate in our patients, which is far lower than that reported elsewhere. The implications are discussed together with identifying strategies for increasing compliance.

Administration, Oral↗
PubMed1997

[Scoring system of late effects of radiations on normal tissues: the SOMA-LENT scale].

Radiation tolerance of normal tissues remains the limiting factor for delivering tumoricidal dose. The late toxicity of normal tissues is the most critical element of an irradiation: somatic, functional and structural alterations occur during the actual treatment itself, but late effects manifest months to years after acute effects heal, and may progress with time. The optimal therapeutic ratio ultimately requires not only complete tumor clearance, but also minimal residual injury to surrounding vital normal tissues. The disparity between the intensity of acute and late effects and the inability to predict the eventual manifestations of late normal tissue injury has made radiation oncologists recognize the importance of careful patient follow-up. There is so far no uniform toxicity scoring system to compare several clinical studies in the absence of a "common toxicity language". This justifies the need to establish a precise evaluation system for the analysis of late effects of radiation on normal tissues. The SOMA/LENT scoring system results from an international collaboration. European Organization Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) have created subcommittees with the aim of addressing the question of standardized toxic effects criteria. This effort appeared as a necessity to standardize and improve the data recording, to then describe and evaluate uniform toxicity at regular time intervals. The current proposed scale is not yet validated, and should be used cautiously.

Humans↗
PubMed1997

Predicting realistic RBE values for clinically relevant radiotherapy schedules.

To consider the therapeutic potential of radiation effect modifiers it is necessary to balance the modification of the injury in tumours with that in different types of normal tissue. It is especially important to ensure that the effects that have been demonstrated in preclinical experiments are both qualitatively and quantitatively relevant for the radiation doses that will be used in clinical schedules. Most radiobiology studies are initially performed with large single doses or a few large fractions, and from those results predictions have sometimes been made of the potential clinical benefit from a radiation modifier. In the clinic they will be used with many repeated small fractions of about 2 Gy over a period of several weeks. The effects will be quantitatively different in these two dose ranges for a variety of reasons. No modifiers of radiation effect are truly dose-modifying over the whole dose spectrum. They all have a differential effect on the type of damage inflicted at high and low dose levels, i.e. those described by the linear and quadratic terms in the LQ model. This means that every modifier has a dose or dose per fraction dependence on the magnitude of the sensitization or protection. The details of that dose dependence will vary with the alpha/beta ratio of the tissue under consideration. Furthermore all tissues and tumours contain a mixture of cells, with different proliferative, redox and other characteristics that influence their sensitivity to radiation and their susceptibility to the radiomodifier. The influence of different subsets of cells changes as a fractionated treatment progresses and the sensitive cells are eradicated, leaving more resistant survivors. The overall response to a fractionated schedule then depends critically on whether there is re-assortment of cells from the resistant phase into more sensitive or modifiable phases before the next fraction in the series. In addition, the magnitude of dose modification depends totally on the standard curve against which the comparison is made. The reference standard is different in preclinical laboratory studies and in conventional clinical experience. Those differences must be considered when moving from the laboratory to the clinic and back again. The effect of these different factors is considered using the linear quadratic model to dissect the components. Examples are provided to demonstrate the clinical relevance.

Animals↗
PubMed1997

ARCON--current status: summary of a workshop on preclinical and clinical studies.

The current status of the experimental and clinical studies of ARCON was presented. This is a new approach aimed at increasing the effectiveness of radiotherapy by acceleration in order to avoid tumour cell regeneration during therapy and using two forms of radiosensitizer of hypoxic cells. The background knowledge about human tumour proliferation and oxygenation was expertly reviewed. New experimental data were presented for various aspects of carbogen, Nicotinamide and a range of other potential sensitizers. These included mechanistic investigations, radiobiological studies of clinically relevant dose levels, tumour and normal tissue effects, pharmacology and blood flow measurements. Clinical data for both toxicity and initial estimates of the tumour response were presented. Extensive discussions about the side effects of Nicotinamide took place. The main conclusions from the preliminary clinical results were encouraging, especially in head and neck and bladder tumours. Two studies showed that local control is considerably increased compared with previous experience and with results from centres of excellence elsewhere. Several other clinicians reported optimism. So far, ARCON has not been taken into randomized clinical trials and the data are therefore still, of necessity, compared with historical controls or with general clinical experience.

Animals↗
PubMed1996

The broad spectrum of preclinical radiobiology: British contributions.

British radiobiologists have often been at the forefront in taking clinical questions into the laboratory and in taking the results back into the clinic, i.e., what is nowadays labeled as Translational Research. They have published widely and have been very active in lectures, workshops, and discussions, forming an important component of the international communication web, both within the basic science aspects and in the translation from science to medicine, and back again. Major contributions have been made at the cellular and subcellular level, and at the level of multicellular structures, both normal and malignant. The common features of the response of cells to single doses in well-defined conditions have been used to interpret the much greater complexity of tissue and tumor responses treated with repeated small doses in a fractionated course, both of photons and other radiations, with and without chemical modifiers. The many contributions to the field of cell kinetics have provided the tools with which an understanding has been gained of the latency and evolution of radiation damage in different tissues. The prolonged interest in microenvironmental gradients and compensatory responses to injury have provided a framework for designing better radiotherapy schedules, and considerable spin-off to other branches of cancer therapy.

History, 20th Century↗
PubMed1996

Radiosensitisation in normal tissues with oxygen, carbogen or nicotinamide: therapeutic gain comparisons for fractionated x-ray schedules.

METHODS: Radiosensitisation with oxygen, carbogen or nicotinamide alone and oxygen or carbogen combined with nicotinamide was compared in early and late responding normal tissues in rodents. X-ray treatments were delivered as single doses or fractionated schedules of 2 fractions in 1 day, 2, 12 and 36 fractions in an overall time of 12 days and 10 fractions in 5 or 12 days. Acute skin reactions, survival of intestinal crypts, breathing rate, reduction in the packed red-cell volume and clearance of 51Cr-EDTA were used as assays of epidermal, gut, lung and renal damage. RESULTS: Relative to air-breathing mice, carbogen or oxygen produced a small, and not always significant, increase in sensitivity (enhancement ratios < or = 1.15) in gut, lung and kidneys; however, in skin a dose enhancement of 1.2-1.3 was observed. The effect of nicotinamide in air, carbogen or oxygen was studied only in lung and gut. The drug produced variable but generally significant increases in radiosensitisation ( < or = 1.26) in all three gases. Relative to treatments in air, enhancement ratios for nicotinamide alone were usually slightly higher than those observed when either carbogen or oxygen were administered without the drug. With all three modifiers (i.e. oxygen, carbogen, nicotinamide alone or for the drug-gas combinations) there was no significant change in the enhancement ratios observed as the number of radiation dose fractions was varied. CONCLUSIONS: Comparisons with fractionated X-ray studies done previously in rodent tumours indicate that a therapeutic benefit, relative to lung, gut and renal damage, would be observed with oxygen or carbogen alone but not with nicotinamide alone. The greatest gain would be achieved with the combination of carbogen and nicotinamide, with which a benefit was observed even relative to epidermal damage. These results indicate that some decrease in normal tissue tolerance could be observed when using these modifiers in clinical radiotherapy and, although small, the appropriate dose reductions should be considered; caution should be exercised especially when carbogen and nicotinamide are used in conjunction with the more radical accelerated schedules.

Animals↗
PubMed1996

Nicotinamide as a repair inhibitor in vivo: studies using single and fractionated X-ray doses in mouse skin and kidneys.

Inhibitors of adenosine diphosphoribosyl transferase, like nicotinamide, 3-aminobenzamide and other analogues, can inhibit repair of radiation-induced sublethal and/or potentially lethal damage in some in vitro systems. Therefore, we have tested the effect of nicotinamide on repair parameters in vivo in two rodent normal tissues. In skin, the sensitivity to dose fractionation (1, 2, 5 or 10 X-ray fractions in 5 days) was monitored by defining the alpha/beta ratio in the presence or absence of nicotinamide (0.5 mg g-1) in air or carbogen. Pre- and postirradiation sensitization were investigated using an X-ray schedule of 5 fractions/5 days in carbogen alone or combined with nicotinamide given 1 h before, immediately after or 8 h after irradiation. Also, changes in the steepness of the underlying X-ray survival curve for the target skin clonogens, reflected by a change in the alpha/beta ratio, were investigated using the neutron top-up design. Underlying survival curves for oxygen +/- nicotinamide were obtained over the X-ray dose range 2.5 to 25 Gy, by administering single X-ray doses and following these with single top-up doses of d(4)-Be neutrons. Finally, in mouse kidney, recovery half-times (t1/2) were obtained by determining the time-dependent disappearance of X-ray damage using a split-dose design of two 6-Gy fractions separated by an interval which varied from 0 to 48 h and followed by two top-up doses from a neutron beam. No increase in alpha/beta for epidermal damage was seen with nicotinamide alone and, although sensitization was observed when the drug was given 1 h before irradiation, no postirradiation sensitization was detected. In kidney, there was no significant difference in the proportion of total repairable damage or in the half-life of recovery between treatments given with or without nicotinamide. Therefore, no decrease in normal tissue tolerance should be observed with the use of nicotinamide in clinical radiotherapy resulting either from reduced sparing with dose fractionation or from an increase in residual damage when shortening the interfraction interval. Finally, unless repair of radiation damage in normal tissues in vivo differs markedly from that of tumors, it is unlikely that the large sensitization seen in rodent tumors at 1.5 to 2 Gy per fraction, with carbogen and nicotinamide, can be attributed to nicotinamide acting as a repair inhibitor.

Animals↗