Might intrinsic radioresistance of human tumour cells be induced by radiation?

Survival measurements were made on six human tumour cell lines in vitro after irradiation with single doses of X rays. Doses up to 5 Gy were used giving surviving fractions down to 20%, but the majority of the measurements were made at doses < 1 Gy. These six cell lines have very different intrinsic radiosensitivities: HT29, Be11, and RT112 are radioresistant with surviving fractions at 2 Gy (SF2) between 60 and 74%, while MeWo, SW48, and HX142 are radiosensitive (SF2 = 3-29%). For all the cell lines, response over the dose range 2-5 Gy showed a good fit to a Linear-Quadratic (LQ) model. However, HT29, Be11, and RT112 cells showed a significant increase in X-ray radiosensitivity at doses below < 1 Gy compared with the prediction extrapolated from a LQ model fitted to the data at higher doses. The LQ model also slightly underpredicted the effect of low-dose X rays in MeWo cells, but the response of SW48 and HX142 cells was well described by the LQ model at all doses, with no evidence of increased low-dose effectiveness. The most plausible explanation for this phenomenon is that it reflects an induced radioresistance so that low doses of X-rays in vitro are more effective per Gy than higher doses, because only at higher doses is there sufficient damage to trigger repair systems or other radioprotective mechanisms. It follows that variation in the amount of inducible radioresistance might explain, in part, differences in intrinsic radiosensitivity above > 1 Gy between cell lines: cells would be intrinsically radiosensitive because they have a diminished inducible response.     

The effect of radiation on tumour growth delay, cell survival and cure of the animal using a single tumour system

The response of a murine tumour to single doses of X rays has been measured using three different assays--animal cure, cell survival in vitro after irradiation in vivo, and tumour growth delay. The dose to cure 50% of the animals, the TCD50, was 79.0 Gy. This was not affected by clamping the tumours to render all the cells hypoxic at the time of irradiation, implying that most of the cells in the tumour were hypoxic already. The enhancement ratio for the hypoxic cell sensitizer Ro-07-0582 was 2.1. The cell survival assay gave an enhancement ratio of 1.6 and an hypoxic fraction of 5%. The discrepancy in the estimates of the hypoxic fraction can be explained by the ability of the naturally hypoxic cells, but not the oxic ones, to recover from potentially lethal damage in vivo. Neither the cell survival assay nor the growth delay assay agreed with the TCD50 assay as to the effect of the hypoxic cell sensitizer, even allowing for recovery from potentially lethal damage. It is doubtful whether the measured survival curve would predict the measured TCD50.     

Radiobiologically based assessments of the net costs of fractionated focal radiotherapy

PURPOSE: To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. METHODS: Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. RESULTS: The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. CONCLUSIONS: Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time.     

Cells at intermediate oxygen levels can be more important than the "hypoxic fraction" in determining tumor response to fractionated radiotherapy

The presence of hypoxic cells in human tumors is thought to be one of the principal reasons for the failure of radiation therapy. Intensive laboratory and clinical efforts to overcome tumor hypoxia have focused on oxygenating, radiosensitizing or killing the maximally radioresistant fraction of tumor cells. This "hypoxic fraction" dominates the single-dose radiation response, irrespective of the oxygenation status of the remainder of the tumor cell population. However, at doses that are typical of those delivered in a daily radiotherapy protocol, we show that the tumor response is highly dependent upon the cells at oxygen levels intermediate between fully oxygenated and hypoxic (0.5-20 mm Hg). For most tumors, these cells are more important than the radiobiologically hypoxic cells in determining treatment outcome after 30 fractions of 2 Gy. We also show that under conditions of diffusion-limited hypoxia, the impact of full reoxygenation between fractions is much smaller than previously realized. Together, the results imply that tumor hypoxia plays a more significant role in determining the outcome of fractionated radiotherapy than previous measurements and assumptions of hypoxic fractions have indicated. Therefore, the concept of a hypoxic fraction in human tumors is less meaningful when pertaining to a fractionated radiotherapy regimen, and should not be expected to be useful for predicting tumor responses in the clinic. This implies the need to characterize tumor oxygenation in a manner that reflects the true oxygenation status of all the tumor cells, not just the ones most refractory to the effects of ionizing radiation. Furthermore, effective therapeutic agents must have the ability to specifically sensitize or kill those cells at intermediate levels of oxygen in addition to the radiobiologically hypoxic cells.     

Effects of low radiation doses on Chinese hamster cells

The induction of cytogenetic damages after irradiation with single dose of gamma-rays (0.1-2 Gy) have been studied. It is shown non-linear curve for the induction of chromosome aberrations, detected by anaphase method. After irradiation in S-stage of the cell cycle at dose below 0.2 Gy the cells were more radiosensitive than after irradiation with doses 0.3-2 Gy. Between the phases of high radiosensitivity and radioresistance the reversal dose-effect relation was observed. This phenomenon was not marked for the cells after irradiation in G2-stage of the cell cycle. It is possible, this results could reflect an induced radioresistance at low dose of irradiation.     

Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

PURPOSE: 5,6-dimethylxanthenone-4-acetic acid (DMXAA) selectively damages tumor vasculature and is currently in clinical trial as an antitumor agent. Its ability to induce synthesis of tumor necrosis factor (TNF), and its apparent selectivity for poorly-perfused regions in tumors, suggests it possible use in combination with radiotherapy. This investigation examines activity of DMXAA as a radiation modifier using two murine tumors. METHODS AND MATERIALS: Tumor growth delay was evaluated using i.m. RIF-1 and MDAH-MCa-4 tumors irradiated in unanaesthetised, restrained mice (cobalt-60) using single dose or multiple fractions (8 x 2.5 Gy over 4 days) with DMXAA administered i.p. at various times in relation to irradiation. RESULTS: Administration of DMXAA (80 micromol/kg, i.p.) immediately after radiation resulted in a large increase in tumor growth delay, giving a radiation dose modifying factor of 2.3 for RIF-1 and 3.9 for MDAH-MCa-4. The combination was less active when radiation was given 1-4 h after DMXAA, but was highly active 12-48 h after DMXAA. At the latter times, clamping the tumor blood supply caused a large increase in radioresistance. These studies suggest that cells surviving DMXAA are hypoxic for only a short period. DMXAA increased overall growth delay when administered daily during fractionated irradiation, giving an approximately additive response. CONCLUSIONS: The marked synergy between DMXAA and single dose ionising radiation may reflect the complementarity of these agents at the microregional level, with DMXAA preferentially killing hypoxic cells in poorly perfused regions. Despite additional hypoxia shortly after DMXAA treatment, surviving cells appear to reoxygenate quickly which makes it feasible to use DMXAA before and during fractionated radiotherapy. The combination of fractionated radiation and DMXAA appears to be less effective than for single dose radiation (possibly because of the smaller contribution of hypoxia under these conditions), but may be therapeutically useful.     

Gel electrophoresis of individual cells to quantify hypoxic fraction in human breast cancers

A new gel electrophoresis method has been used to quantify hypoxic fraction in human tumors. Radiation-induced DNA damage was measured in individual tumor cells, where the radiobiologically hypoxic cells were observed as a subpopulation showing a 3-fold reduction in DNA strand breaks. Patients receiving palliative radiotherapy for breast cancers were given a single dose of 5-10 Gy, and a fine needle aspiration biopsy was taken immediately after irradiation. Hypoxic cells were detected in seven of eight tumors. In four tumors, bivariate analyses of DNA content versus DNA damage to individual cells allowed distinction between the response of diploid normal cells and aneuploid tumor cells. These early results indicate that "comet assay" shows considerable promise for resolving the extent and significance of hypoxia in human tumors.     

Comparison between the in vitro intrinsic radiation sensitivity of human soft tissue sarcoma and breast cancer cell lines

The purpose of this study is to evaluate the radiation sensitivity of human soft tissue sarcoma cell lines in vitro and to compare with that of human breast carcinoma and glioblastoma cell lines. The intrinsic radiation sensitivity parameters of seven human soft tissue sarcomas and eight breast carcinoma cell lines were investigated in vitro by clonogenic assays for single-dose irradiation under aerobic conditions on cells in exponential phase of growth. The results for sarcoma cell lines showed that the mean surviving fraction at 2 Gy (SF2) was 0.39 (SD +/- 0.09) with a range of 0.24 to 0.53, and the average mean inactivation dose (MID) was 1.92 (SD +/- 0.35) range from 1.36 Gy to 2.49 Gy. These values were not different from that of breast cell lines examined concurrently and using the same experimental methods (mean SF2 0.38, SD +/- 0.09; MID 1.9 Gy, SD +/- 0.37). However radiobiological parameters of nine karyotyped human malignant glioma cell lines determined earlier in this laboratory were significantly higher (mean SF2 0.50 +/- 0.14; mean MID 2.61 +/- 0.60). In conclusion, the data presented here do not support the view that cells of sarcomas show unusual radiation resistance. To the extent that the in vitro determined cellular radiation sensitivity reflects the tumor response in vivo, the success rate for radiation applied against sarcoma and breast carcinoma of comparable size could be similar.     

Fluconazole sensitivities of Candida species isolated from the mouths of terminally ill cancer patients

BACKGROUND: It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to "curative" regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with "curative" fractionation schedules in human squamous cell carcinoma in nude mice. MATERIAL AND METHODS: FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD50 values, i.e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks. RESULTS: TCD50 values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD50 after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD50 with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). alpha/beta eff determined from all data was 58 Gy (13; infinite). CONCLUSIONS: The results of the present study compare well with our previous findings after different "curative" fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and "curative" regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.     

Enhancement of fractionated-dose irradiation by retinoic acid plus interferon

PURPOSE: To evaluate the relative cytotoxicity of fractionated-dose radiation in the presence and absence of 13-cis-retinoic acid (RA) plus alpha-2a-interferon (IFN), as a function of overall treatment time. METHODS AND MATERIALS: Studies were performed with the human squamous cell carcinoma line FaDu, in vitro. Attached exponential phase cells were treated with RA + IFN for 8-10 h and then exposed to single graded doses of radiation, or 1 to 6 doses of radiation at 2 Gy per dose, or to 5 doses of radiation at 2 Gy/dose with a time interval of 4-24 h between treatments. Following irradiation, the cells were incubated with drugs present throughout colony formation, and the fraction of survivors in the presence and absence of the combined drugs was calculated. RESULTS: For single graded-dose irradiation, the surviving fraction ratio at 2 Gy in the absence vs. presence of drugs was 1.27 +/- 0.19 in 3 repeat experiments. Following administration of 6 doses of radiation at 2 Gy/fraction with a 5-h time interval between treatments and, after correcting for cell proliferation between treatments, the surviving fractions differed by a factor of 3.25, again indicating an average difference in survival of 1.26 after each of the 6 2-Gy/fractions. Treatment with 5 2-Gy doses of irradiation with 24 vs. 4 h elapsing between doses, resulted in a 3-fold greater decrease in survival in the presence of drugs vs. no drug. The relatively greater cell kill due to 24 vs. 4 h between treatments was due to drug inhibition of cell proliferation between the more prolonged treatments. CONCLUSIONS: The results of this study indicate that retinoic acid plus interferon both sensitizes and inhibits cell proliferation during treatment. These results suggest that this combination of radiation and drugs, when used concurrently, may be effective for inhibiting tumor cell proliferation or accelerated repopulation during clinical fractionated radiotherapy.     

Perceptions of tonal changes in normal laryngeal, esophageal, and artificial laryngeal male Cantonese speakers

PURPOSE: Present radiobiological studies for different cell lines in vitro demonstrate the equivalence and efficacy of continuous low-dose-rate brachytherapy (LDR-BT) and pulsed dose rate brachytherapy (PDR-BT) when using small and frequent dose pulses. The aim of this study was to examine monolayer fibroblast cultures in vitro to examine the biological effects of different pulse doses and dose rates under clinically conditions. MATERIAL AND METHODS: B14 cells, Hy B14 FAF 28, peritoneal fibroblasts, were cultured in multi-well plates and exposed to a PDR radiation source at a distance of 9 mm. The following PDR-schemes were compared: dose per pulse: 1 Gy, 2.5 Gy and 5 Gy to a total dose of 5 Gy/5 h (overall time), 10 Gy/10 h, 20 Gy/20 h and 30 Gy/30 h. The pulse duration for the examination of dose rate effects was 20 min, 30 min or 52 min corresponding by dye pulse dose rate of 300 cGy/h, 200 cGy/h or 115 cGy/h. Treatment endpoints were cell measured by dye exclusion test and clonogenic cell survival. RESULTS: Cell survival decreased for pulse doses of 5 Gy compared to 2.5 Gy or 1 Gy per pulse (mean dose rate 200 to 300 cGy/h). No differences were observed with dose rates during irradiation of 300 cGy/h, 200 cGy/h or 115 cGy/h (20 Gy/1 Gy). CONCLUSION: Radiobiological effects of PDR-RT are dependent on the dose per pulse, with differences in biological effects only with a dose per pulse of more than 2.5 Gy, considering the described in-vitro conditions. More examinations with a more pronounced difference in dose rate will be continued for evaluation of dose rate effects.     

Radiosensitivity of new and established human melanoma cell lines: comparison of [3H]thymidine incorporation and soft agar clonogenic assays

Seven new low-passage melanoma lines were developed in this laboratory from clinical melanoma specimens and characterised for chromosome complement, DNA ploidy and S-phase content. The radiosensitivity of these lines was compared with that of eight established melanoma cell lines, FME, MM-96, SK-MEL-5, SK-MEL-28, SK-MEL-2, MALME-3M, M19-MEL and LOX-IMVI, using a 96-well microculture assay technique. Dose-response curves were determined using a 5-day incubation period and 6-h terminal [3H]thymidine-labelling period. Radiation (60Co source) was carried out under a lead wedge to provide a radiation dose range of 0-10 Gy, or by irradiating part of the plate (radiation dose 0 or 2 Gy). Data for a range of cell densities in a single 96-well plate were combined into a single regression equation incorporating linear quadratic terms for radiation dose and cell density. SF2 values were defined as the amount of thymidine incorporated following a radiation dose of 2 Gy, expressed as a fraction of that of unirradiated cells, and varied from 0.36 to 0.93. The reproducibility in repeat assays, as defined by the standard error of determinations at different passage numbers, was +/- 0.04. The newly developed lines exhibited a similar range of radiosensitivity to that of the established lines, and melanin content did not correlate with resistance. For nine of the lines, radiation parameters were also determined using a modified Courtenay clonogenic soft agar assay technique, and the results compared with the thymidine incorporation results, and a significant linear correlation was found between SF2 and SF2' (r = 0.89). The linear (alpha) and quadratic (beta) terms of the best-fit linear quadratic dose-response curves, were significantly correlated between the two assays. It is concluded for this series of human melanoma lines that proliferation assays in 96-well plates provide radiosensitivity parameters comparable to those using clonogenic assays.     

Proliferation and clonal survival of human lung cancer cells treated with fractionated irradiation in combination with paclitaxel

PURPOSE: This study was performed to determine the effects of a continuous exposure to paclitaxel (taxol) in combination with fractionated irradiation on cell proliferation and survival. METHODS AND MATERIALS: Human lung carcinoma cells (SW1573) were given a daily treatment with 3 Gy of x-rays during 5 days in the continuous presence of 5 nM taxol. The surviving fraction and the total number of cells were determined every 24 h before and immediately after irradiation. RESULTS: Irradiation with 5 x 3 Gy and 5 nM taxol cause approximately the same inhibition of cell proliferation. In combination these treatments have an additional effect and the cell population increases no further after the first 24 h. Whereas the cells become more resistant to taxol after the first 24 h with a minimum survival of 42%, taxol progressively reduces the population of surviving cells in combination with x-rays when the number of fractions increases, up to 25-fold relative to irradiation alone. The enhancement effect of 5 nM taxol is likely to be attributed to an inhibition of the repopulation during fractionated irradiation and not to an increased radiosensitivity. Only after treatment with 10 or 100 nM taxol for 24 h, which is attended with a high cytotoxicity, is moderate radiosensitization observed. CONCLUSION: Taxol, continuously present at a low concentration with little cytotoxicity, causes a progressive reduction of the surviving cell population in combination with fractionated irradiation, mainly by an inhibition of the repopulation of surviving cells between the dose fractions.     

Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment

PURPOSE: With regard to the poor prognosis of patients with glioblastoma multiforme, the aspect of life quality with a minimal treatment time becomes essential. The purpose of the present study is to evaluate whether the results of a radiotherapy schedule using increased single fractions applied over a shortened treatment time is feasible without compromising treatment efficiency or providing more side effects than a conventionally fractionated treatment. PATIENTS AND METHODS: A total of 38 patients (f = 21, m = 17, mean age 58 years) with histologically proven glioblastoma multiforme were irradiated after (partial) resection (n = 29) or stereotactic surgery (n = 9) with single doses of 3.5 Gy (ICRU) 5 fractions a week up to a total dose of 42 Gy following individual treatment planning. RESULTS: Median survival was 45.7 weeks, survival rate after 6 months was 80.9% and decreased to 34.2% after 12 months. Radiotherapy was tolerated without any important acute toxicity or any late side effects during the follow-up period. CONCLUSIONS: The increase of the dose per fraction using a fraction size of 3.5 Gy enhanced neither acute nor late toxicity. The survival rate compared well to those described in the literature. Thus the shortened treatment schedule seems as efficient as conventional radiotherapy. Moreover, it seems preferable with regard to quality of life.     

A quantitative assay for assessing allelic proportions by iterative gap ligation

PURPOSE: We compared gastrointestinal toxicity of single vs. fractionated total body irradiation (TBI) administered at dose rates ranging from 0.021 to 0.75 Gy/min in a canine model of marrow transplantation. METHODS AND MATERIALS: Dogs were given otherwise marrow-lethal single or fractionated TBI from dual 60Co sources at total doses ranging from 8-18 Gy and delivered at dose rates of 0.021, 0.05, 0.10, 0.20, 0.40, and 0.75 Gy/min, respectively. They were protected from marrow death by infusion of previously stored autologous marrow cells and they were given intensive supportive care posttransplant. The study endpoint was 10-day mortality from gastrointestinal toxicity. Logistic regression analyses were used to jointly evaluate the effects of dose rate, total dose, and delivery regimen on toxicity. RESULTS AND CONCLUSION: With increasing dose rates, mortality increased for either mode of delivery of TBI. With dose rates through 0.10 Gy/min, mortality among dogs given single vs. fractionated TBI appeared comparable. Beginning at 0.20 Gy/min, fractionation appeared protective for the gastrointestinal tract. Results in dogs given TBI at 0.40 and 0.75 Gy/min, respectively, were comparable, and dose fractionation permitted the administration of considerably higher total doses of TBI than were possible after single doses, an increment that was on the order of 4.00 Gy. The data indicate that the impact of fractionating the total dose at high dose rates differs from the effect of fractionation at low dose rates.     

The response of human tumour blood flow to a fractionated course of thermoradiotherapy

The response of human tumour blood flow to a fractionated course of thermoradiotherapy was documented in four superficial but bulky tumours (three adenocarcinomas, one melanoma). Blood flow was measured 15, 30, 45, and 60 min after the onset of heating. These measurements were made at the same intra-tumour point during each heat fraction by use of a modified thermal clearance technique in which a correction was made for the heat dissipated by thermal conduction. This point was at least 2 cm beneath the surface in the central portion of the tumour. Extracellular pH was measured within 1 cm of this point prior to the first heat fraction and 2-3 weeks later. Hyperthermia was administered for 60 min, twice a week for 4 weeks by use of a 16-channel 915 MHz microwave applicator. Each patient also received a radiation dose of 40 Gy fractionated at 2 Gy/fx, five times a week (adenocarcinomas) or 4 Gy/fx, twice a week (melanoma). Blood flow remained relatively constant during heating after steady state conditions were attained. However, an overall decrease in tumour blood flow was observed in each patient over the course of thermoradiotherapy. In each case, a relatively small decrease in blood flow occurred between most heat fractions which resulted in an overall decrease which ranged from 50-100%. However, there was a tendency for blood flow to increase following the initial heat fraction at points where the steady state temperature was approximately 41 degrees C or less. Extracellular pH increased in two of three patients and decreased in the other.     

Sensitivity of human prostatic carcinoma cell lines to low dose rate radiation exposure

PURPOSE: Low dose rate radioemitters, such as 125I, 103Pd, and 89Sr, have been used both for local and systemic treatment of prostate cancer. Most normal cells exposed to ionizing radiation characteristically activate cell cycle checkpoints, resulting in cell cycle arrest at the G1/S and G2/M transition points. Cancer cells are typically quite sensitive to radiation killing late in the G2 phase of the replicative cell cycle. Furthermore, most cancer cells accumulating at the G2/M transition point as a result of low dose rate radiation exposure appear to become sensitive to further low dose rate irradiation. For this reason, protracted exposure of cancer cells to low dose rate radiation has been proposed to result in increased cancer cell killing as compared with brief exposures of cancer cells to high dose rate radiation. Since many human prostatic carcinomas contain somatic genome alterations targeting genes which affect the cell cycle and radiation-associated cell cycle checkpoints, we evaluated the effects of low dose rate radiation exposure on the cell cycle and on clonogenic survival for various human prostatic carcinoma cell lines. MATERIALS AND METHODS: Human prostatic carcinoma cells from the LNCaP, DU 145, PC-3, PPC-1, and TSU-Pr1 cell lines were exposed to low dose rate (0.25 Gy/hour) or high dose rate (60 Gy/hour) radiation in vitro and then assessed for radiation cytotoxicity by clonogenic survival assay. Cell cycle perturbations following protracted exposure to low dose rate radiation were evaluated using flow cytometry. RESULTS: For LNCaP cells, low dose rate radiation exposure resulted in an accumulation of cells at both the G1/S and the G2/M cell cycle transition points. For DU 145, PC-3, PPC-1, and TSU-Pr1 cells, treatment with low dose rate radiation triggered G2/M cell cycle arrest, but not G1/S arrest. Unexpectedly, the cell cycle redistribution pattern phenotypes observed, G1/S and G2/M cell cycle arrest versus G2/M arrest alone, appeared to have little effect on low dose rate radiation survival. Furthermore, while PC-3, PPC-1, and TSU-Pr1 cells exhibited increased cytotoxic sensitivity to low dose rate versus fractionated high dose rate radiation treatment, DU 145 and LNCaP cells did not. CONCLUSIONS: Radiation-associated pertubations in replicative cell cycle progression were not dominant determinants of low dose rate radiation killing efficacy in human prostate cancer cell lines in vitro.     

The role of sulfation and/or acetylation in the metabolism of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Salmonella typhimurium and isolated rat hepatocytes

The efficacy of repopulation during treatment splits in conventional radiotherapy (5 fractions/week, 2.5, 3.5, 4.5 Gy/fraction) was studied by delayed top-up treatment of mouse tongue epithelium. Splits of 6 h to 13 days were introduced after 1 or 2 weeks of fractionated irradiation. Following 5 fractions, compensation of about 3 dose fractions was assessed after the first weekend and original tissue tolerance was restored after a split of 4-10 days. About 4.6 dose fractions were repopulated during the second treatment week, followed by a further 1.5 fractions during the first 3 split days; restoration of the initial tolerance required 3-8 days. These results indicate that repopulation was more efficient during fractionated radiotherapy than during a subsequent treatment split. Latent times to complete denudation after the top-up treatment decreased to a dose-dependent minimum after 5 fractions and remained at the decreased level when a second treatment week was added. Original values were restored within 5-8 days after 5 fractions and 6 days after 10 fractions. Epithelial cell density during treatment with 3 or 4 Gy/fraction decreased to a dose-dependent nadir of 63% and 52% of the original number after 5 fractions, and original cell counts were then restored after 5 days. Cellularity remained at 60-70% during the second treatment week and subsequently reached normal values within 4 days. In conclusion, reconstitution of epithelial cellularity precedes restoration of radiation tolerance during treatment splits.     

The fate of retained gallstones following laparoscopic cholecystectomy in a prairie dog model

By extrapolation to zero time, the initial and final slopes of data sets which probably demonstrate the existence of accelerated repopulation during radiotherapy can be used to estimate the lower limits of the initial tumour hypoxic fraction. The slow repopulation phase (initial slope) is assumed to reflect treatment in mixed oxic and hypoxic conditions and the later fast repopulation (final slope) phase that of a well-oxygenated cell population. The method assumes that accelerated repopulation in tumours results from an improvement in oxygen status during radiotherapy, but quantitative knowledge of repopulation factors is not required in the calculations. Using the data of (a) Withers et al. (for head and neck squamous cell cancer) and (b) Maciejewski & Majewski (for bladder cancer), the lower limits of initial hypoxic fraction appear to be between 10 and 52%, the exact values depending on the value assumed for the oxygen-enhancement ratio (OER) of the hypoxic compartment. The analysis also suggests that the half-life of effective tumour reoxygenation is probably less than 5 days.