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Biomedical subjects

G G Steel

Publications and source records attributed to G G Steel.

At least 109 records · Page 6Linked to original sources
PubMed1983

The response to chemotherapy of a variety of human tumour xenografts.

The results of a series of projects on the cytotoxic drug response of human tumour xenografts are compared. All were performed in one laboratory, using conventional CBA mice that were usually immunosuppressed by thymectomy, cytosine arabinoside treatment, and whole-body irradiation. Results on human tumours arising in 9 anatomical sites are included, with the main emphasis on colo-rectal, pancreas, breast, lung and testis carcinomas, also melanomas. Growth acceleration during successive passage of most of these tumour types was observed. When therapeutic response was measured by a growth-delay method there were wide differences in response to chemotherapy. Testicular teratomas and small-cell lung tumours responded well; breast tumours showed modest response; melanomas, colo-rectal tumours and non-small-cell lung tumours responded poorly. Studies of clonogenic cell survival were made in 11 xenografted tumour lines. They confirmed the range of responsiveness and tendency towards individuality of the growth delay data. Cell survival in most cases was exponentially related to drug dose. This compilation of a large amount of experimental data supports the belief that human tumour xenografts broadly maintain the level of chemotherapeutic responsiveness of the source tumours in man.

Animals↗
PubMed1983

The relationship between 'early' and 'late' radiation-induced skin reactions as seen in two strains of mice that differ in radiosensitivity.

The acute skin reaction and time-course of skin contraction following graded single doses of X-rays were studied in CBA and C57B1 mice, in order to elucidate the relationship between 'early' and 'late' skin damage in strains that are known to differ in radiosensitivity. A dose-dependent acute reaction and rapid skin contraction was noted 0-50 days after irradiation in both strains, and both parameters of response were greatest in the C57B1 mice. Following this initial shrinkage there was a slight relaxation, which was again more evident in the C57s. A gradual, continuous, dose-independent contraction from 50-466 days was evident in CBA mice, whereas in C57s there was no evidence of late shrinkage. Histological examination at 466 days post-irradiation revealed a greater epidermal hyperplasia in CBA than in C57 mice. Comparison of these results with data on acute intestinal damage and early and late lung damage shows no general relationship between the incidence of early and late radiation damage in these two strains of mice.

Acute Disease↗
PubMed1983

Bleomycin and radiation-induced lung damage in mice.

Bleomycin-induced lung damage was assessed using both a functional end-point and mortality. The extent of lung damage was found to depend on the schedule, mode of administration and dose of the drug. Greater damage occurred following twice-weekly administration than when the same dose was given as a single injection. Intravenous administration resulted in greater damage than intraperitoneal administration. When bleomycin was given with thoracic irradiation lung damage occurred earlier and at lower radiation doses than with radiation alone. Similar responses were obtained whether bleomycin was given four weeks before, with or four weeks after irradiation. Thus although there was enhanced damage from the combined treatment, there was no evidence of a time-dependent interaction.

Animals↗
PubMed1983

The expression of early and late damage after thoracic irradiation: a comparison between CBA and C57B1 mice.

Lung injury after localized irradiation of the thorax was quantified and compared in CBA and C57B1 mice. Using lethality and breathing rate as end points, two phases of damage separated in time were distinguished in CBA mice as an early pneumonitic phase and a later phase associated with pleural effusions. C57B1 mice failed to show the pneumonitic response over a large dose range extending beyond 20 Gy. In this respect they differ from most other mouse strains so far studied. At the lower doses the extent of the late phase was similar between these two strains. The interstrain comparison presented suggests that damage to separate tissue compartments was responsible for the acute and chronic responses.

Animals↗
PubMed1982

Experimental combination and single-agent chemotherapy in human lung-tumour xenografts.

A series of human bronchial-carcinoma xenografts (3 small-cell anaplastic, 2 large-cell anaplastic and 3 adenocarcinomas) established in immune-suppressed mice were treated with combination chemotherapy based on clinical regimes. Xenograft response was assessed by the in situ endpoint of growth delay in s.c. tumours. Dose-response relationships of 3 triple-drug combinations and their component agents were explored, allowing the relative contributions of single agents in each combination to be assessed. The results demonstrate that the effects produced in the xenografts were generally consistent with clinical experience. Procarbazine, cyclophosphamide and CCNU stood out as the most effective drugs in small cell carcinoma, but were ineffective in the other histological types. These was some evidence for individuality of therapeutic response among the grafts, supporting the case for incorporating panels of histologically similar xenografts into primary drug-screening programmes to complement existing syngeneic rodent tumour systems.

Adenocarcinoma↗
PubMed1982

Response of two mouse tumours to hyperthermia with CCNU or melphalan.

The in vivo response of B16 melanoma and Lewis lung carcinoma to combinations of hyperthermia and graded doses of CCNU or Melphalan was studied. To obtain dose-response curves and quantitative comparisons of different treatments, an agar-colony assay was used to measure survival of cells from excised tumours. For heating experiments, the use of 2 tumours per animal, one heated and one not, allowed all other factors to be kept constant. When tumours were immersed in a water-bath at 43 degrees C for 1 h, Thermal Enhancement Ratios (TER) measured from the slopes of the dose-response curves were up to 1.6 for CCNU and 2.4 for Melphalan. Direct heat killing of about 1 decade was seen for 1 h at 43 degrees C. The anaesthetic Saffan also enhanced drug cell kill; the largest Dose Modifying Factor (2.7) was measured for Melphalan in the Lewis lung tumour. The duration of heating, and waterbath temperature, both influenced the enhancement of cell killing by CCNU, as did the time of excision of tumours between 0 and 3 1/2 h after treatment. There was no difference in effect between 3 1/2 and 24 h. The interaction between heat and CCNU varied if the interval between them was altered. The maximum effect was found if the heat and drug were given in close sequence.

Animals↗
PubMed1982

Dose-dependence of the time of appearance of lung damage in mice given thoracic irradiation.

Male CBA mice were given X-radiation to the thorax in the range 7 to 23 Gy and their response was quantified by measuring ventilation rate and carbon monoxide uptake at intervals up to 2 years thereafter; their survival was also documented. The two functional end-points were similarly sensitive indicators of lung damage. Radiation damage was not observed below 10 Gy. As radiation dose was raised above this level there was a rapid shortening of the time to the appearance of damage and subsequent death. At a dose of 15 Gy the median survival time was 14 weeks but raising the dose above this level only slightly reduced the survival time. The way in which the time of survival after lung damage depends on dose is an important characteristic of the development of radiation-induced lung damage which should be considered when examining factors that may influence the development of radiation-induced lung damage.

Animals↗
PubMed1982

Use of the agar diffusion chamber for the exposure of human tumor cells to drugs.

Human melanoma xenografts in immune-deprived mice have been used to assess the value of the agar diffusion chamber for chemosensitivity testing. Tumor cells were treated with melphalan, Adriamycin, or methyl trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea either as solid tumors growing in mice or as suspensions in agar in i.p. diffusion chambers. Survival of clonogenic human tumor cells was measured by the agar diffusion chamber assay in both cases. Cell survival curves were log-linear for treatment of tumor cells in vivo or in the chambers. For melphalan the slopes of survival curves were significantly greater for treatment in the chambers than as solid tumors in vivo, but for methyl trans-1-(2-chloroethyl(-3-(4-methylcyclohexyl)-1-nitrosourea or Adriamycin, they were indistinguishable. Experiments with [14C]melphalan showed that the levels of drug achieved were less inside the diffusion chambers than in the tumors in vivo so that the sensitivity of tumor cells to melphalan was much greater when they were treated in chambers. The differences in drug exposure and in cellular chemosensitivity between chambers and tumors suggest caution in the interpretation of drug testing using this system, but the log-linear nature of the dose-response curves is an important feature which may be useful in the eventual development of optimal chemosensitivity testing systems.

Agar↗
PubMed1981

Clonogenic cell survival in cryopreserved human tumour cells.

Cells from 3 human tumours have been grown in soft agar contained in Millipore diffusion chambers and implanted i.p. in mice. Clonal growth was obtained from fresh biopsy samples, from cryopreserved tissue, and from xenografts of the tissues in immune-suppressed mice. The radiosensitivities of a melanoma and an ovarian carcinoma were evaluated by in vitro irradiation before assay for colony formation. Xenografting did not modify the radiosensitivity of the melanoma. Cells from another tumour were exposed to Adriamycin or cyclophosphamide whilst contained within i.p. diffusion chambers; the sensitivity was similar for cryopreserved and xenografted cells. The results encourage further attempts to quantify the sensitivity of human tumour cells by these methods.

Animals↗
PubMed1980

The human tumour xenograft--a valid model in experimental chemotherapy?

The chemotherapeutic response of a series of patients with bronchial carcinoma has been compared with the response of their xenografts established in immune-suppressed mice. The in situ endpoint of growth delay in subcutaneous tumours was the main parameter used to assess xenograft response, but clonogenic cell survival studies were also performed to assess the extent of cell kill associated with in vivo responses. Histology, chromosome analysis and demonstration of ectopic hormone production indicated that the xenografts retained human morphology and functional behaviour. Clinical response was assessed by serial measurement of metastases. The chemotherapeutic validity of xenografts is supported by this study in which 21 separate responses in 16 patients and their respective xenografts were similar. Metastases regressed completely in 5 out of 7 patients with oat cell carcinoma. Xenografts derived from these were also highly responsive to similar chemotherapy. In contrast, minimal responses were observed in xenografts established from two chemoresistant patients. One large cell anaplastic, 3 squamous and 4 adenocarcinomas were universally chemoresistant in patients and their xenografts. It is concluded that the bronchial carcinoma xenografts broadly retained human morphology and functional behaviour, and reproduced the pattern of chemotherapeutic response of their source tumours. The present work suggests that the incorporation of human tumour xenografts into drug development programmes is justified, although their usefulness in a predictive capacity to select appropriate chemotherapy for individual patients remains limited.

Animals↗
PubMed1980

Colony growth and clonogenic cell survival in human melanoma xenografts treated with chemotherapy.

A soft-agar diffusion-chamber technique was used to grow colonies from human melanoma xenografts. Plating efficiencies ranged from 0-042% to 75% and increased with serial passage of some tumours. Cells in colonies were similar to human melanoma cells in morphology, histochemistry and ultrastructure, and were shown by immunofluorescence to contain human antigens. Xenograft tumours could be regrown from the colonies when re-implanted into immune-deprived mice. Cell-survival curves were constructed from 5 xenograft lines treated with 4 cytotoxic drugs. All lines were resistant to adriamycin, but each line appeared to have an individual spectrum of sensitivity to the more effective drugs. The responses were compatible with the clinical pattern of response in melanoma, and in 2 cases the objective response of lung metastases to treatment with melphalan was consistent with the xenograft cell-survival data. Dose-response curves were exponential for treatment with methyl-CCNU and melphalan, but distinct plateaux were seen for 2 xenografts treated with doses of DTIC over 100 mg/kg. These were thought to be due to resistant subpopulations of clonogenic cells within the tumours.

Animals↗
PubMed1980

Chemotherapy of human breast-carcinoma xenografts.

Five lines of human breast-carcinoma xenografts have been tested for sensitivity to cyclophosphamide, methotrexate, 5-fluorouracil, adriamycin, vincristine and melphalan, alone and in combination, using tumour growth delay as an end-point. The xenograft lines were established and passaged in mice immune-suppressed by thymectomy and whole-body irradiation. There was a considerable range of sensitivity of the different lines to the agents studied, and within this variation there was evidence that the most effective single agent or combination differed for each tumour. Combination chemotherapy was more effective than single agents in 3 of the lines, but melphalan was more effective than either combination in the other 2. It is suggested that a panel of human breast tumours grown in immune-suppressed mice may prove useful in testing new cytotoxic agents for activity against breast cancer before their use in clinical trials, and that more effective combinations of existing drugs might be designed with the aid of this system.

Animals↗
PubMed1980

In vitro chemosensitivity tests on xenografted human melanomas.

An in vitro chemosensitivity test has been applied to malignant melanoma cells from 5 patients. The tumour cells were first grown as xenografts in immune-suppressed mice, so that the results of the in vitro test could be compared with precise measurements of the sensitivity of the melanoma cells when exposed to chemotherapeutic drugs in vivo in the mouse. The in vitro assay involved exposing the tumour cells to each of 8 drugs, after which cell survival was determined by colony assay in soft agar. Dose-response curves were obtained and the surviving fraction at drug levels estimated to be achieved in man was used as a measure of in vitro drug sensitivity. Significant differences among the 8 drugs were detected, and these accorded with clinical experience. The correlation of in vivo (in the mouse) and in vitro sensitivities to Melphalan and MeCCNU was also significant.

Animals↗
PubMed1980

The therapeutic response of bronchial carcinoma xenografts: a direct patient-xenograft comparison.

The chemotherapeutic response of a series of patients with bronchial carcinoma has been compared with the response of their xenografts established in immune-suppressed CBA/lac mice. Xenograft response was assessed by the in situ endpoint of growth delay in subcutaneous tumours. Histology and chromosome analysis indicated that human characteristics were retained in the xenografts. 49 xenograft lines were attempted: 15/18 oat cell, 11/17 squamous, 6/8 large cell anaplastic and 6/6 adenocarcinomas were successfully established. 14 Lines (28%) were available (August 1979) for direct comparison of xenograft and donor patient response to the same chemotherapeutic agents. A positive correlation was found and provides support for the chemotherapeutic validity of xenografts.

Animals↗
PubMed1980

Human tumour xenografts: a critical appraisal.

Human tumours grown in immune-deficient mice are available for studies in experimental pathology and therapeutics. In addition to growth-delay experiments clonogenic assays can sometimes be performed. Xenografts often retain some characteristics of the source tumour but the amount of precise information on the maintenance of therapeutic sensitivity is small. Principal drawbacks include the difficulty of matching with human doses the dose of drugs given to the host mouse, and the probable existence of a substantial host reaction against the grafts. Principal benefits may be to studies that involve the intercomparison of human tumours in regard to therapeutic response.

Animals↗