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Biomedical subjects

G G Steel

Publications and source records attributed to G G Steel.

At least 91 records · Page 5Linked to original sources
PubMed1986

Temporal interactions in the Lewis lung tumour between cytotoxic drugs and acute or fractionated radiotherapy.

The suggestion was examined, that acute irradiation might be combined with some cytotoxic drugs to produce a supra-additive antitumour effect by timing the second treatment to coincide with the period of repopulation by tumour cells that survived the first treatment. The possible interaction of fractionated irradiation with drugs was also studied. Lewis lung tumours were treated in vivo with acute radiation (20 Gy) and 1-(2-chloroethyl)-3-(4-methyl cyclohexyl)-1-nitrosourea (MeCCNU, 10 mg X kg-1), cyclophosphamide (CY, 120 mg X kg-1) or cis-dichlorodiammine platinum (cis-Pt, 10 mg X kg-1) with time intervals ranging from simultaneous to 9 days in either sequence. Tumour response was measured by regrowth delay and combination responses were evaluated relative to calculated "additivity envelopes". With CY and cis-Pt, tumour volume response was approximately additive, whether the drugs were administered simultaneously, or up to 7 days before or after radiation. However, with simultaneous administration, MeCCNU and radiation were supra-additive in terms of volume response, although only additive using a clonogenic cell survival assay. A transplantation experiment suggested that the supra-additive volume response may be due to retarded growth rate in regrowing tumours. In the fractionation studies, drugs were given either at the beginning or at the end of a regime of 5 daily 6 Gy doses. With CY and MeCCNU the drugs were more effective when given with the first radiation dose, but with cis-Pt either regime was equally effective. There was no evidence that repopulation could be exploited to improve therapeutic effect with any of the combination treatments used in this study.

Animals↗
PubMed1986

Dose-rate effects and the repair of radiation damage.

The extent of dose-sparing that occurs in a variety of cell lines and in vivo cell systems as a result of a reduction in dose-rate is reviewed. The emphasis is on the range from around 200 cGy/min down to 5 cGy/min, in which the predominant reason for dose-sparing is the repair of radiation damage. Dose-rate dependence is considered in relation to the Lethal-Potentially Lethal model of cell inactivation, which satisfactorily fits 4 sets of data that we have tested; estimates of half-time for repair varied from 0.07 to 1.4 h. The model shows that in spite of these short half-times, repair will often continue to influence response down to dose-rates below 5 cGy/min. The steepness of the dose-rate dependence varies widely among in vitro cell lines and among mouse normal tissues, indeed the ranges in vitro and in vivo are similar. Haemopoietic tissues are much less spared by a lowering of dose-rate than are other normal tissues. Uncertainties about the rate of reoxygenation preclude similar considerations in experimental tumours in vivo. There is a need for detailed studies of dose-rate dependence in human tumour cell lines, and the present review outlines the basis (including the optimum dose-rate range) for such studies.

Animals↗
PubMed1986

Clonal variation in the sensitivity of a murine mammary carcinoma to melphalan.

The sensitivity to melphalan of clones derived from individual lung colonies produced by i.v. injection of cells of the MT murine mammary carcinoma (caMT) and its melphalan-resistant sub-line (MTME16) has been examined. A degree of clonal heterogeneity was observed which was greater than could be explained by experimental variation. The distribution of melphalan sensitivities in both wild-type caMT and MTME16 raises questions as to the validity of a two-compartment model of drug-resistance development in tumours. A more complex model, possibly involving a continuous spectrum of drug sensitivity, is required. Differences in the sensitivity of the clonal lines of wild-type caMT in various passages were observed and this would appear to be due to phenotypic instability in these lines. This suggests that to use survival data from clones which have been passaged many times for predicting the response of the parent tumour may be misleading.

Animals↗
PubMed1986

Autoradiographic analysis of the cell cycle: Howard and Pelc to the present day.

Although flow cytometry has become the popular way to examine the kinetics of cell proliferation, the technique of labelled mitoses remains an important and central technique. This is particularly the case when it is the durations of cell cycle phases that are required. Through simulation analysis it is possible to identify discrepancies that imply the existence either of artefacts or of unsuspected properties of the cell system under investigation: the implications of these discrepancies have often been inadequately explored. An important function of the modelling approach is to seek to identify aspects of the data that cannot be fitted, and to pursue the discrepancies either by eliminating artefacts or by seeking to describe a more comprehensive model.

Animals↗
PubMed1985

Adriamycin sensitivity following "ultra" low dose rate irradiation of Lewis lung carcinoma in vivo.

As an extension of recent study on the response of the Lewis lung tumor to low dose rate continuous irradiation (CI) at 15 cGy/hr, we have gone on to investigate the effects of such irradiation on the sensitivity of tumor cells to treatment with Adriamycin (Adr). Cells from untreated tumors gave an exponential dose response curve to Adr in vitro, the D10 of which increased (sensitivity decreased) with the size of tumor (0.05 g to 0.6 g) from which the cells were obtained. After previous in vivo CI to a total dose of 28 Gy (irradiation time--186 hr), this size dependence was abolished and the cells showed an exponential response to Adr in vitro (D10 = 0.4 microgram/ml). The enhancement was also observed after equivalent doses of fractionated irradiation, but not after acute irradiation. It was difficult to characterize the proliferative status of the cells surviving irradiation, but repopulation studies showed that only after CI was there any delay before repopulation commenced. LL was relatively insensitive to Adr in vivo, however, we did observe an increased effect after previous CI.

Animals↗
PubMed1985

Development of drug resistance in a murine mammary tumour.

The development of resistance to melphalan, cis-platinum and cyclophosphamide has been examined in the MT murine mammary carcinoma. A gradual decrease in therapeutic response was detected using growth delay and clonogenic cell survival during repeated drug treatment. A slow rate of resistance development, a gradual change in the slope of the dose-survival curves and the inability of 180 mg kg-1 cyclophosphamide to bring about a reduction in tumour response at a faster rate than 60 mg kg-1 cyclophosphamide suggest that resistance development was not due to the selection of a pre-existing highly drug resistant sub-population of tumour cells. Partial drug-resistance is proposed as one possible reason for the apparent inconsistency between these data and existing models of drug-resistance development. The drug-resistant lines were characterized for karyotype, DNA content and cell volume, but only the cyclophosphamide-resistant line showed any significant difference from the wild-type tumour. Cross-resistance studies revealed some inconsistencies with previous reports. Also, resistance to cyclophosphamide developed more quickly in the line which was resistant to melphalan, than in the wild-type tumour, despite the initial appearance of little cross-resistance. This increased rate of resistance development may be important in salvage chemotherapy.

Animals↗
PubMed1985

Resistance to alkylating agents and tumour differentiation in xenografts of small cell lung cancer.

Small cell bronchial carcinoma (SCC) xenografts with differing sensitivity to cyclophosphamide (CY) were investigated using a variety of techniques. Two xenografts (HX78 and HX88) were relatively sensitive to CY, one xenograft (HX72) was inherently resistant to CY and a fourth xenograft (HX78Cy) was a CY induced resistant subline of HX78 and was unstable when maintained without CY exposure. Conventional light microscopy, cytology and electron microscopy examination of the xenografts revealed appearances consistent with SCC. An antikeratin antibody demonstrated the presence of keratin in the inherent and the induced resistant xenografts (and in the unstable revertant) but not in the two sensitive xenografts; the presence of keratin suggested squamous differentiation. Monolayer culture morphology of the sensitive HX78 and the unstable revertant was anchorage independent with the cells forming floating aggregates; the induced resistant subline of this xenograft (HX78Cy) showed, by contrast, flattened, angular adherent cells. Beta HCG production was detected in the monolayer culture supernatant of sensitive HX78 cells; the level of production of beta HCG was increased in the induced resistant HX78Cy cells. Karyotype and flow cytometry studies were also performed. The morphological responses of small cell lung cancer to treatment are discussed.

Animals↗
PubMed1984

Cell survival in four ovarian carcinoma xenografts following in vitro exposure to melphalan, cisplatin and cis-diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA,JM8).

Four human ovarian carcinoma xenografts were established and maintained in immune-suppressed mice. Cells obtained from these xenografts were exposed in vitro to melphalan, JM8, and cisplatin; cell survival following a 1-h exposure was measured using a soft-agar colony assay. A similar dose-response curve was obtained with melphalan for each of the four xenografts, despite previous treatment with an alkylating agent in two of the patients from whom the xenografts originated. Cell survival was also compared after JM8 and cisplatin exposure in each individual xenograft. It was found to be similar for each tumour when the concentrations of JM8 used were 10-fold greater than those of cisplatin. Early clinical studies in which JM8 has been shown to be effective in the treatment of ovarian carcinoma support the view that xenograft tumours may have a role in phase-II screening of new cytotoxic agents.

Animals↗
PubMed1984

Chemotherapy in combination with pelvic irradiation: a time-dependence study in mice.

The importance of timing of drug administration in combination with pelvic irradiation on animal lethality was investigated in male CBA mice. The chemotherapeutic agents cyclophosphamide, cytosine arabinoside, 5-fluorouracil, methotrexate, cis-dichlorodiammine platinum (II), adriamycin, CCNU, VP-16 and bleomycin were administered at various times up to 2 weeks before and 2 weeks after pelvic irradiation (4 weeks before and after in the case of cyclophosphamide) of unanaesthetised mice and the LD50/30 days and dose enhancement factors determined. The results indicate a potentiation of radiation-induced damage when drugs are given near to the time of irradiation, particularly at about 3 days post-irradiation.

Animals↗
PubMed1984

The radioresponsiveness of human tumours and the initial slope of the cell survival curve.

Published data on the inherent radiosensitivity of human tumour cells has been analysed in order to reexamine the relationship between the initial slope of the cell survival curve and clinical radioresponsiveness. A clear positive correlation between these parameters is demonstrated. The surviving fraction at 2 Gy is shown to give good discrimination between resistant and sensitive tumour types.

Cell Line↗
PubMed1984

Induced and inherent resistance to alkylating agents in human small-cell bronchial carcinoma xenografts.

Inherent and induced resistance was investigated in human small-cell lung cancer xenografts. Specimens from three patients were established in immune suppressed mice; the sensitivity of the xenografts to cyclophosphamide, MeCCNU and melphalan was determined using the growth delay end-point. Clinical chemosensitivity data were available in two cases and inherent differences in sensitivity were noted both in the xenografts and clinically. Radioactively labelled melphalan uptake studies were performed with these two xenografts. A number of different strategies to induce resistance were explored. Only one method proved to be successful and in only one of the xenografts; this was with cyclophosphamide. The induced resistant line was characterised in terms of the time course of its production, the degree of induced resistance, the growth rate, the cross-resistance pattern and stability of the phenotype; the possibility of altered antigenicity was also examined.

Alkylating Agents↗
PubMed1984

Oxygen-dependent protection of radiation lung damage in mice by WR 2721.

The modification of early and late radiation damage to the mouse lung by oxygen and WR 2721 has been studied by measurement of breathing rate, lethality, pleural fluid and hydroxyproline content. Protection by hypoxia and sensitization by hyperoxia of early radiation pneumonitis were demonstrated. There was a tendency for the protective effect of WR 2721 to decrease as the breathed oxygen concentration was raised above normal levels. WR 2721 protection of the late damage was higher (PF = 1.6-1.65) than was seen for early pneumonitis (PF = 1.3-1.35) when either breathing rate or lethality were used. Protection factors (PF) gained from measurements of pleural fluid at a year after treatment were similar to those for other endpoints of late damage (PF = 1.7). In contrast, the measurement of fibrosis through determination of lung hydroxyproline at 1 year gave a somewhat lower protection factor for WR 2721. In the same experiments the degree of epilation on the dorsal thorax was scored at 6 weeks. One hundred per cent oxygen gave enhancement (dose enhancement factor (DEF) = 1.2), 9 per cent oxygen reduced damage (DEF less than 0.7) and WR 2721 gave PF values in excess of 1.4 at all oxygen concentrations used. This showed that the radiation response of hair follicles was more sensitive to WR 2721 or to changes of oxygen than the lung. The results presented indicate a competitive interaction between WR 2721 and oxygen for the same injury site causing a shift in the oxygen K curve to higher oxygen concentrations. The validity of applying functional or survival measurements to assess the extent of pulmonary fibrosis is discussed.

Amifostine↗
PubMed1984

Response to continuous irradiation (CI) in relation to the initial slope of the cell survival curve for tumours and bone marrow.

In vivo ultra low dose rate continuous irradiation (CI, 15 cGy h-1) was used in an attempt to accurately quantify low dose radiation response (less than 2 Gy) of both tumour and normal tissue, a parameter which is clinically relevant but difficult to assess using conventional acute radiation survival curves. Dorsally placed tumours were irradiated by housing tumour bearing mice for up to three weeks in a dedicated 137Cs unit taking care to shield the lower body. Response to CI was monitored by an excision cell survival assay. For bone marrow treatment whole body irradiation was used and BM-CFUc were assessed. In all 4 tissues studied (Lewis lung carcinoma, B16 melanoma, carcinoma MT and C57B1/6 bone marrow) cell survival decreased exponentially with dose; the three tumours had similar D0 (approximately 6 Gy), bone marrow was more sensitive (D0 1.5 Gy). Acute in vitro radiation survival curves were analysed using both the multi-target plus single hit and the linear quadratic models of radiation cell kill. Comparison of CI results with acute radiation survival curve parameters derived from each model suggest that CI offers a useful means of assessing the low dose radiosensitivity of tumours and may therefore be useful in the prediction of tumour response to clinically relevant fractionated treatments.

Animals↗
PubMed1983

The effects of anesthetics and misonidazole on the development of radiation-induced lung damage in mice.

The measurement of breathing frequency as a functional end-point of radiation-induced lung injury in mice allowed two phases of damage to be discerned; the first was manifest at 12-20 weeks after irradiation, the second beyond 28 weeks. Anesthesia by pentobarbitone sodium or steroids gave significant radioprotection of the lung during the early pneumonitic phase. Addition of the hypoxic cell sensitizer misonidazole removed the protective influence of the anesthetics but did not sensitize the lungs of unanesthetized mice. No anesthetic protection was detected for the late response, showing evidence for dissociation between early and late lung damage. The degree of epilation was measured on the dorsal thoracic region of the same mice. Protection by anesthetics and its reversal by misonidazole was also demonstrated. These results provide a warning of potential hazards in the laboratory evaluation of chemical radiosensitizers. The use of anesthetics at the time of irradiation could lead to an exaggerated enhancement of normal tissue damage.

Adrenal Cortex Hormones↗
PubMed1983

Lung damage in mice from cyclophosphamide and thoracic irradiation: the effect of timing.

The development of lung damage in mice following thoracic irradiation is enhanced by cyclophosphamide (CY). CY was given at various times from 28 days before to 28 days after irradiation. Although increased damage was seen at all times, the extent showed marked variation according to the time interval. The most marked variations were seen when CY was given within 24 hours of irradiation; maximal enhancement was seen when CY was given before or with irradiation and minimal response when given 12 hrs before or 12 hrs after irradiation. It may therefore be prudent for the clinician to avoid such close time intervals between cytotoxic drugs and irradiation, unless a specific time-related therapeutic gain can be exploited.

Animals↗
PubMed1983

Continuous irradiation of the Lewis lung carcinoma in vivo at clinically-used "ultra" low-dose-rates.

The in vivo response of the transplantable Lewis lung tumor to continuous irradiation (CI) at the clinical "ultra" low-dose-rates of 10-30 cGy/h was investigated. Tumor-bearing mice were housed in a dedicated 137Cs unit for up to three weeks while receiving CI. The horizontal 137Cs beam allowed secondary shielding of the lower body, but full irradiation of the dorsally-placed tumor and part of the upper body. Radiation survival curves were measured using an excision assay and tumor-cell colony formation in soft agar. The relative cell survival per tumor decreased exponentially with time and the irradiation periods required to reach a surviving fraction of 10(3) at the three dose-rates (10, 15 and 30 cGy/h) were 15.4, 10.2 and 4.3 days. As a function of dose, the survival curves were exponential and indistinguishable between the three dose-rates, the average DO value being 5.04 Gy. Neither the hypoxic fraction of the tumor nor the intrinsic cellular radiosensitivity were altered in the tumor cells surviving CI. The effects of the three dose-rates on the growth of Lewis lung tumors differed considerably, with clear volume regression at the highest dose rate (30 cGy/h) and exponential decreases in clonogenic cells per tumor with time at 15 and 30 cGy/h. Since the overall effect of CI is determined by the competition between cell killing and cell repopulation, the response of slowly-growing human tumors should be proportionately greater.

Animals↗