Radiation Response Of Tissues Research Articles

Modification of Radiation Response: Cytokines, Growth Factors, and Other Biological Targets

From the contents: Normal Tissues: Role of Radiation-Induced Signaling Proteins in the Response of Repopulating Normal Tissues Role of Radiation-Induced Signaling Proteins in the Response of Vascular and Connective Tissues Pathogenetic Mechanisms of Lung Fibrosis Strategies for Modification of the Radiation Response of the Lung Strategies for Modification of the Radiation Response of Gastrointestinal Organs Mechanisms and Modification of the Radiation Response of the CNS Haematopoetic Tissue I: Response Modification by EPO Haematopoetic Tissue II: Role of Colony-Stimulating Factors Oral Mucosa: Response Modification by Keratinocyte Growth Factor Malignancies: Role of Growth Factors in Tumor Growth and Progression (incl. GYN Tumors) CNS Tumors Lung, Head and Neck, GI Tumors Role of Signalling Pathway Modification Anti-VEGT Strategies plus Radiotherapy Anti-EGFR Strategies plus Radiotherapy and further 5 chapters, Subject Index and List of Contributors.

Radiation injury and the protein C pathway.

To summarize current knowledge regarding the role of the thrombomodulin (TM)-protein C system in acute and chronic radiation responses in normal tissues. Studies published in the biomedical literature during the past three decades and cited in PubMed and unpublished clinical and laboratory data from our own research program. STUDY SUMMARY: The risk of injury to normal tissues limits the cancer cure rates that can be achieved with radiation therapy. Microvascular injury is a prominent feature of normal tissue radiation injury and plays a critical role in both acute (inflammatory) and chronic (fibrotic) radiation responses. Evidence from our own and other laboratories strongly suggests that dysfunction of the TM-protein C system plays a key role in the pathogenesis of radiation-induced injury to normal tissue. Exposure of normal tissues to ionizing radiation causes a pronounced, sustained deficiency of endothelial TM. This is likely to be due to a combination of initial inactivation of TM by reactive oxygen species, reduced transcription of TM, and release of TM into the circulation. Deficient levels of endothelial TM cause loss of local vascular thrombo-resistance, excessive activation of protease-activated receptor-1 by thrombin, and insufficient activation of protein C. These changes are presumed to be critically involved in many aspects of acute radiation toxicity and in sustaining the fibroproliferative processes that lead to chronic radiation-induced organ dysfunction and clinical complications. Injury of vascular endothelium may be key to the acute responses of normal tissues to ionizing radiation and to the progressive nature of chronic radiation fibrosis. Restitution of the TM-protein C pathway is an appealing strategy by which to prevent or treat normal tissue toxicity associated with radiation treatment of cancer.

Increased IL-6 and TGF-β1 concentrations in bronchoalveolar lavage fluid associated with thoracic radiotherapy

PurposeTo assess, in lung cancer patients, the effects of thoracic radiotherapy (RT) on the concentrations of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) in the bronchoalveolar lavage (BAL) fluid. Methods and materialsEleven patients with lung cancer requiring RT as part of their treatment were studied. BAL was performed bilaterally before, during, and 1, 3, and 6 months after RT. Before each BAL session, the patient's status was assessed clinically using pulmonary function tests and an adapted late effects on normal tissue-subjective, objective, management, analytic (LENT-SOMA) scale, including subjective and objective alterations. The National Cancer Institute Common Toxicity Criteria were used to grade pneumonitis. The TGF-β1 and IL-6 levels in the BAL fluid were determined using the Easia kit. ResultsThe TGF-β1 and IL-6 concentrations in the BAL fluid recovered from the irradiated areas were significantly increased by thoracic RT. The increase in TGF-β1 levels tended to be greater in the group of patients who developed severe pneumonitis. In the BAL fluid from the nonirradiated areas, the TGF-β1 and IL-6 concentrations remained unchanged. ConclusionThe observed increase in TGF-β1 and IL-6 concentrations in the BAL fluid recovered from the irradiated lung areas demonstrated that these cytokines may contribute to the process leading to a radiation response in human lung tissue.

Radiation response of hypoxic and generally heterogeneous tissues

Purpose : Biologically based treatment optimisation can be based on the local mean values of the number of clonogenic cells and the cellular radiation response taken over macroscopic tissue voxels. Steep oxygen gradients in tumours may often lead to microscopic distributions of radiation resistance at the cellular level, far beyond the geometrical resolution of current diagnostic and radiotherapeutic methods. The present work focuses on quantifying the radiobiological effect of such microscopic distributions through tissue-oxygenation modelling and on calculating the corresponding radiation response on both micro- and macroscopic scales. Materials and methods : A simple model of tissue vasculature was developed with microvascular density and heterogeneity as its main parameters. New analytical expressions are presented for calculating the effective radiation response of tissues with generally heterogeneous radiation resistance and clonogen density. Results : The oxygen distributions derived for different parameter sets agree very well with clinically measured oxygen distributions for both tumours and normal tissues. In addition to the vascular density, vascular heterogeneity is an important factor while estimating the hypoxic fraction in tissue. It is shown that both the local and global dose-response relation for tissues with heterogeneous radiation resistance can be accurately calculated from the effective initial clonogen number N 0,eff and the effective radiation resistance D 0,eff. New equations are derived for calculating these quantities, for instance, from measured oxygen distributions. Conclusions : With the new methods presented here, existing techniques to measure the micro- and macroscopic oxygen distribution either using standard tumour-type or patient-specific oxygenation data can be used for biologically based treatment plan optimisation.

Effect of keratinocyte growth factor on radiation survival and colony size of human epidermal keratinocytes in vitro.

Keratinocyte growth factor (FGF7, also known as KGF) ameliorates the radiation response of mouse oral mucosa and other epithelial tissues. However, the precise mechanisms remain unclear. The aim of the present study was to investigate the effect of FGF7 on the survival and colony size of normal human epidermal keratinocytes in vitro. Primary neonatal keratinocytes (HEKn) were irradiated with doses of 0 and 2 Gy of 200 kV X rays and incubated in the presence or absence of 100 ng/ml FGF7. The plating efficiency (PE) and surviving fraction (SF2) were determined using a clonogenic assay. In cell cultures without FGF7, the mean PE was 4.6 +/- 0.2%. Irradiation with 2 Gy resulted in an SF2 of 51 +/- 2%. In cell cultures with FGF7, the mean PE was identical, and a similar SF2 of 54 +/- 1% was observed (P = 0.4). However, the individual colony size was significantly increased in all cultures incubated with FGF7 compared to those incubated without FGF7. The number of extremely large colonies (> or =2 mm) was clearly higher (P < 0.0001) in cultures with FGF7. This was accompanied by a significant reduction in the diameter of individual cells from 29 microm in controls to 23 microm with FGF7. In conclusion, FGF7 does not affect the survival of keratinocytes after irradiation, but it does stimulate proliferation of surviving cells.

15.Radiation survival and colony size of human epidermal keratinocytes in the presence of keratinocyte growth factor (rhKGF)

The capacity of recombinant human keratinocyte growth factor (rhKGF) to ameliorate the radiation response of mouse oral mucosa and other epithelial tissues was recently reported. However, the exact mechanisms of action of KGF remain unclear. The aim of the present study was to investigate the effect of rhKGF on survival and colony size of normal human epidermal keratinocytes in vitro. Primary human neonatal keratinocytes (HEKn) were irradiated with doses of 0 Gy and 2 Gy (200 kV X-rays) and incubated in the presence or absence of 100ng/ml rhKGF. Plating efficiency (PE) and surviving fraction (SF2) were determined in a clonogenic assay. In cell cultures without rhKGF the mean PE was 4.6%. Irradiation with 2 Gy resulted in a SF2 of 51%. In cell cultures with rhKGF, the mean PE was identical (4.6%). After irradiation with 2 Gy, a similar SF2 of 54% was observed, indicating that KGF did not change the survival characteristics of HEKn keratinocytes. Individual colony size, however, in all cultures incubated with rhKGF was significantly increased compared to incubation without rhKGF. The number of extremely large colonies (□2 mm) was clearly higher (p=0.0000) with rhKGF-containing culture medium. In conclusion, rhKGF does not affect keratinocyte survival after irradiation, but stimulates proliferation of surviving cells.

Different impact of p53 and p21 on the radiation response of mouse tissues.

Mammalian tissues differ dramatically in their sensitivity to genotoxic stress, although the mechanisms determining these differences remain largely unknown. To analyse the role of p53 and p21 in determination of tissue specificity to DNA damage in vivo, we compared the effects of gamma radiation on DNA synthesis on whole-body sections of wild type, p53-deficient and p21-deficient mice. A dramatic reduction in 14C-thymidine incorporation after gamma irradiation was observed in the majority of rapidly proliferating tissues of wild type and p21-/- but not in p53-/- mice, confirming the key role of p53 in determination of tissue response to genotoxic stress in vivo and suggesting that p53-mediated inhibition of DNA synthesis does not depend on p21. Rapid radiation induced p53-dependent apoptosis was mapped to the areas of high levels of p53 mRNA in radiation sensitive tissues analysed (white pulp in the spleen and bases of crypts in small intestine), indicating that p53 regulation at the mRNA level is a determinant of cellular sensitivity to genotoxic stress. High p53 mRNA expression is inherited as a recessive trait in cell-cell hybrids suggesting the involvement of a negative control mechanism in the regulation of p53 gene expression.

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice.

Boron neutron capture therapy (BNCT) destroys tumor cells by means of α particles and recoil protons emitted by 10B(n,α)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B‐enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7‐ to 2.7‐fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1‐ to 6.9‐fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15–180 min after FAA+BSH, or in those in skin irradiated at 120 and 180 min.

254Predictive assays in radiotherapy The Aarhus experience fibroblast radiosensitivity versus early and late normal tissue radiation response in patients with breast cancer

254Predictive assays in radiotherapy The Aarhus experience fibroblast radiosensitivity versus early and late normal tissue radiation response in patients with breast cancer

Complications of Combined Radiotherapy and Chemotherapy.

The radiation-modifying effect of cancer chemotherapeutic drugs is reviewed based on experimental studies covering skin, esophagus, intestinal tract, lungs, kidney, bladder, testis, and hematopoietic tissue. The results obtained in experimental studies have, whenever possible, been compared with observations of normal tissue reactions in clinical practice. Such a comparison of experimental and clinical data is difficult and should be cautiously interpreted. However, where comparable data are available there seems to be a reasonable agreement between experimental and clinical data. It appears that drugs with an effect on the tissue by itself should especially be expected to enhance the radiation response in that specific tissue. Concerning the importance of the intervals and sequence of the two treatment modalities, experimental data seem to indicate the effect of timing in clinical practice. The best way to avoid enhanced reactions in normal tissues is to separate the two treatment modalities in time and, possibly, to administer chemotherapy before radiotherapy. Experimental data should be cautiously considered, together with clinical experience, in planning of drug-radiation combinations to avoid unacceptable reactions in critical normal tissues. Guidelines for the clinical use of combined radiotherapy and chemotherapy are proposed.

Microdosimetric measurements in the build-up region of very pure high-energy photon and electron beams

A microdosimetric system, specially designed to allow measurements in both the presence and the absence of secondary charged particle equilibrium, has been used to investigate the build-up region of a clean 15 MV bremsstrahlung beam and a 21 MeV almost monoenergetic electron beam. The use of quasi-broad-beam conditions with a split tissue-equivalent phantom and a wall-less chamber surrounded by a low-pressure tissue-equivalent gas minimizes the fluence perturbation, caused by the detector. Along with microdosimetric beam quality data, ordinary dosimetric information can be obtained, together allowing estimation of the properties of the beam with regard to radiation response in tissue. By applying an inversion algorithm on the measured microdosimetric distributions to correct for plural events, it is shown that already at a probability of coinciding pulses as low as 1% the dose mean value of the single-event distributions increases by 3%. The dose mean lineal energy for the pure bremsstrahlung beam is strongly affected by both photon contamination and in-phantom scattering thus being 55% higher close to the surface than near the dose maximum.

Late radiation response of canine mediastinal tissues

The mediastinal tissues which included heart, lung, trachea and esophagus of 70 adult beagle dogs were irradiated to a range of total radiation doses between 24 and 68 Gy given in 2, 3 and 4 Gy fractions. The purpose of the study was the calculation of α β ratios for morphologic and functional changes of the mediastinal tissues. Functional assays including echocardiography, electrocardiography, right heart hemodynamics and cardiac output were performed. Histomorphometric analyses of all tissues included in the field were done 2 years after treatment. Euthanasia was performed on 7 of 70 dogs prior to 2 years due to congestive heart failure and seven other dogs had signs of heart failure 2 years after treatment. Heart failure was thought to be caused by either pericardial effusions or constrictive pericarditis in these dogs. Heart failure occurred at doses of 62 and 68 Gy given in 2 Gy fractions, 60 Gy given in 3 Gy fractions and 52 Gy given in 4 Gy fractions. The ED 50 values for pericardial fibrosis for 2, 3 and 4 Gy fractions were 46.1, 43.9 and 26.6 Gy, respectively. An α β ratio of 2.5 Gy was calculated by direct quantal response analysis. Small foci of myocytolytic lesions were detected in 11 dogs. Calculated ED 50 values for myocytolysis were 70.4 Gy given in 2 Gy fractions and 50.8 Gy given in 4 Gy fractions. The estimated α β ratio was 3.2 Gy. Heart rates determined from physical examination and frequency of S-T segment changes increased with increasing dose. No other dose related changes were found in any of the other functional parameters. Functional changes were detected in the 14 dogs with clinical signs of heart failure. Focal consolidation and subpleural fibrosis were present in the irradiated lung volume. These late changes had no detectable physiologic effect in these dogs because of the small volume of lung irradiated. The ED 50 values for lung consolidation were 54.3, 45.8 and 26.6 Gy after 2, 3 or 4 Gy fractions, respectively. The estimated α β ratio was 3.4 Gy. No dose-related changes could be detected in the trachea or esophagus at 2 years after treatment. These results demonstrate that lung and pericardium are the most responsive tissues in the mediastinum within the first 2 years after treatment. Myocardial lesions were present with high ED 50 values, but were not found to be functionally significant at 2 years after irradiation. Human clinical data indicate that longer observation periods are needed for development of these lesions. The late response of the non-dividing myocytes is likely to be progressive over long periods of time. All α β ratios calculated in this study fell within the range expected for these late responding tissues. These results further emphasize the sparing of function of late normal tissue injury by reducing dose/fraction.

Hydralazine-induced Changes in Tissue Perfusion and Radiation Response in A C3H Mammary Carcinoma and Mouse Normal Tissues

Hydralazine has been reported to reduce blood perfusion in tumours, thereby increasing hypoxia and subsequently enhancing tumour sensitivity to certain drugs and hyperthermia. We have investigated the ability of hydralazine to induce such changes in a C3H mouse mammary carcinoma and various normal tissues. In tumours, hydralazine (5 mg/kg; i.v.) modified the radiation response, measured by a local tumour control assay, producing an effect equivalent to that seen in tumours made fully hypoxic by clamping. This effect was time-dependent and correlated with the decrease in tissue perfusion estimated by the 86-RbCl extraction procedure. Similar effects were seen in normal skin, although the changes were less dramatic and of a shorter duration. Hydralazine also reduced 86-RbCl uptake in liver, kidney, gut and spleen, but not in bladder, muscle and lung, suggesting that it may have the potential to increase the sensitivity of some normal tissues to hypoxic cell cytotoxins.

Response of Human Organs to Single (or Fractionated Equivalent) Doses of Irradiation

Characteristics of the kinetics of radiation response of human tissues and organs are exemplified by effects in the testis and the ovary. Also, published dose-incidence curves for specified levels of injury in bone marrow, liver, bladder and lung are characterised in terms of single doses as well as single-dose equivalents calculated from fractionated doses using the alpha/beta equation. It is shown that these curves, analysed using a Poisson model, have slopes characterised by D0-equivalents ranging between 1.25 and 2.5 Gy. These values are higher or within the range of values reported in general for single-dose survival curves of human cells in primary culture (range of D0 values 0.7-1.8 Gy). This indicates that single-cell responses together with other complicating biological and statistical sources of heterogeneity under discussion, could form a basis for explaining the steepness of dose-incidence curves for organ injury after fractionated doses. With local organ irradiation, increase in the single-dose equivalent by 3-10 per cent would increase the complication rate from 5 per cent to 10 per cent. Higher dosage increases (by up to two times) apply to fractionated doses.

Assay of Radiation Effects in Mouse Skin as Expressed in Wound Healing

The effect of 150 kVp X irradiation on the healing of full depth surgical wounds in the lower dorsal skin of the mouse was assayed by measuring the wound strength of seven 2-mm-wide segments along each wound. The strength of unirradiated wounds increased with time in two phases: during the first 2 weeks it reached nearly half of the values recorded from unwounded skin, after which the rate of increase slowed for at least 2 weeks before beginning a second increase. By 150 days, the breaking strength of the wound was about 80% of that of unwounded skin. A single dose of 18 Gy prior to wounding reduced the strength of the wounds to about one-third to one-half that of an unirradiated wounds within the 3 months of follow-up. The effect of irradiation on wound strength did not change as the interval between exposure and wounding was increased to 2 months but decreased slightly when this interval was extended to 3 months. When the healing wound was irradiated within 5 days of surgery, the effect on healing was about the same as with preirradiation; if irradiation was delayed for 12 days after wounding the second phase of healing was only postponed and the wound strength ultimately approached the values recorded from unirradiated wounds. The wound strength of skin preirradiated by X rays and assayed 14 days after wounding showed a clear sigmoid dose response with a threshold between 8 and 10 Gy and a plateau at the maximum effect above 20 Gy. The persistence for at least 3 months of the effect of radiation on wound healing suggests that the tissues involved in the healing process are normally proliferating slowly. The accelerated expression of radiation injury through surgical wounding permits the early quantification of the radiation response of tissues that would normally be delayed in their expression of radiation damage.

Treatment volume and tissue tolerance

Hypotheses regarding tissue organization and radiation response were described and, on the basis of simple modeling, tentative conclusions were drawn regarding the influence on “tolerance” doses of tissue organization and the volume of an organ irradiated. (1) A functional subunit (FSU) may be defined structurally (e.g. as in a nephron), or only functionally, as the largest unit of cells capable of being regenerated from a surviving clonogenic cell without loss of the specified function. (2) Functional subunits may be arranged in parallel or in series: in parallel they give rise to graded dose responses, whereas in series, they give rise to threshold binary, or quantum responses. (3) Tolerance doses are a function of the number and radiosensitivity of target cells in an FSU, tissue organization and the functional reserve (i.e. the proportion of functional subunits necessary for adequate organ function). (4) An influence of treatment volume on “tolerance” doses is more likely to depend upon tissue organization than upon differences in cellular radiosensitivity. (5) The volume of tissue irradiated would be expected to be irrelevant to the “tolerance” of tissues showing a graded dose response (e.g. skin desquamation), except when the injury becomes severe, when tolerance for a large severe wound is likely to be less than for a small volume of injury, for non-radiobiological reasons. (6) Tissues with FSU's arranged in series, for example, spinal cord or peritoneal sheath along small bowel, should show a threshold-binary response. Sigmoid dose response curves should have a lower threshold and be steeper the larger the treatment volume. The effect of increase in volume is greatest with changes in small volumes: once a large number of FSU's are being irradiated, a further increase in volume has little effect on the position or slope of the probability curve for such complications. (7) Because their sigmoid dose-response curves are steep, threshold-binary tissues are sensitive to small increases in “biologically effective” dose. For example, when the spinal cord is treated with large dose fractions the biological effectiveness per unit of dose increases sharply. Thus, using a large volume together with large dose fractions, as could happen in palliative prescriptions, could augment the danger of myelitis. (8) Because of the low density of cells potentially the “targets” for peritoneal adhesion formation and small bowel obstruction, and because a measurable incidence of obstruction is usually already “tolerated,” the most marked effect of changes of treatment volume on complications in clinical practice may be found with postoperative abdominal and pelvic irradiation.

Biochemistry of reduction of nitro heterocycles

Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (i.e. deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in early and late effects with dose-per-fraction: Alpha, beta, redistribution and repair

Both tumor response and the manifestation of “early“ and ”late“ effects in normal tissues as a function of overall treatment time and dose per fraction are thought to reflect an interplay between the inherent sensitivity of the target cells at risk, and their proliferation kinetics. In light of clinical and experimental studies which indicate that differences exist between early and late radiation responses in normal tissues after changes in fractionation pattern, several investigators have postulated that the intrinsic sensitivities of the respective target cells, in particular the α/β ratios, are different. We suggest that the clinical and experimental findings may be explained, at feast partly, in terms of cell cycle redistribution, and may also involve changes in the ability of early effects target cells to repair potentially lethal damage.

Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships

Clinical and experimental evidence for divergent changes in early and late radiation responses in normal tissues after changes in dose fractionation indicate a greater sensitivity of late responses to changes in dose per fraction. In experimental studies of the effect of dose per fraction on early and late isoeffects, a larger number-of-fractions exponent for the late responses is the rule. These findings imply that the shape of the dose-survival curve for the target cells whose depletion results in late effects is different from that for target cells for acute effects: as the dose increases the contribution to cell killing from accumulated sublethal injury, relative to killing from single hit events, increases more rapidly in the target cells for late effects. In other words, the survival curve for the target cells for late injury must be “curvier” than that for acute effects. Although such survival curve characteristics are independent of the survival curve model chosen to describe them, they would represent, in terms of the parameters of the linear quadratic model, S = e − αD− βD 2, a higher β α ratio for late effects. If the dose survival characteristics of tumor clonogens resemble those of the target cells in acutely responding normal tissues, and if late injury in normal tissues is dose-limiting, then a therapeutic gain would result from reducing the size of dose per fraction by hyperfractionation. Conversely, increasing the size of dose per fraction should reduce the therapeutic differential.

ICRF-159 enhancement of radiation response in combined modality therapies. II. Differential responses of tumour and normal tissues.

The combined effect of the chemotherapeutic agent ICRF-159 and radiation on the proliferative status of tumor/normal systems has been evaluated using the Lewis lung tumour in BDF1 mice. We have previously shown that a 25 mg/kg dose of ICRF-159, given at 3h intervals X4 before irradiation, significantly enhanced tumour growth retardation relative to a single dose of 100 mg/kg before irradiation. Whilst both single and fractionated drug treatments produced a transient inhibition of cell proliferation, comparisons of the temporal recovery from the antiproliferative effect of radiation in both tumour and intestinal epithelium suggested that single acute doses of ICRF-159 fail to potentiate the radiation response of either tissue. Protracted drug administration before irradiation, however, markedly decreases the post-radiation proliferative recovery of the tumour, without significantly altering intestinal recovery. The data suggest that both drug concentration and/or exposure time determine the interactions seen with combined modes.