The utility of cell kinetic data in the design of therapeutic schedules.
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Antineoplastic Agents↗
Biomedical subjects
G G Steel
Publications and source records attributed to G G Steel.
Terminology in the description of drug-radiation interactions.
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Animals↗
Changes in lymph node size following systemic irradiation for malignant lymphoma.
Changes in surface area of lymph nodes visualised on abdominal radiographs following lymphography were measured in 18 patients treated by systemic irradiation for non-Hodgkin's lymphoma. Eleven radiologically normal nodes in testicular tumour patients receiving higher doses of external irradiation were measured for comparison. Following lymphography spontaneous shrinkage by up to 20% of the surface area of the node was observed. Since spontaneous and continual regression of abdominal nodes can occur exceptionally in nodular lymphoma, treatment was deferred until there was evidence of an increase in the size of nodes judged as being involved by lymphoma. Two forms of systemic therapeutic irradiation were employed, total body (TBI) and hemi-body (HBI). The rate of nodal regression with both was comparable but the amount of regression, time to nadir of node size and subsequent growth delay, was greater for HBI than TBI.
Diaphragm↗
Experimental chemotherapy of gastrointestinal carcinoma xenografts.
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Animals↗
Assays of drug sensitivity for cells from human tumours: in vitro and in vivo tests on a xenografted tumour.
A human tumour which grows as a xenograft in immune-suppressed mice and forms colonies in vitro has been used to test the correlation between 2 methods of exposure of human tumour cells to chemotherapeutic agents. In vivo exposure to drugs was achieved by injection of tumour-bearing mice with each of 8 cytotoxic agents. For the in vitro exposure, cell suspensions were incubated for 1 h with the same series of drugs. The survival of tumour clonogenic cells was assayed in vitro after either treatment or dose-response curves were obtained. The 8 drugs were ranked according to their in vivo effect at doses equitoxic to mice, and according to their in vitro effect at concentrations designed to approximate to levels of drugs in human plasma. The ranks for in vivo and in vitro exposure correlated well.
Animals↗
Influence of biogenic amines on the growth of xenografted human colorectal carcinomas.
The influence of some biogenic amines and amine-receptor-blocking drugs in the growth rate of human colorectal carcinomas propagated as s.c. xenografts in immune-deprived mice was studied. In mice treated with adrenaline, a beta-adrenergic agonist, the growth of xenografts was suppressed for 2 days, after which growth was resumed at a rate similar to that in control animals. Treatment with the phosphodiesterase inhibitor theophylline prolonged the adrenaline-induced inhibition of growth. Treatment with the beta-adrenergic antagonist sotalol or practolol increased the rate of tumour growth. Treatment with either serotonin or the histamine H2-receptor agonist Dimiprit had no effect on tumour growth rate. However, the antiserotoninergic drug BW 501C and the histamine H2-receptor antagonist cimetidine each caused short-term suppression of tumour growth.
Adrenergic Agonists↗
The quantitative response of human tumours to radiation and misonidazole.
Eleven patients with measurable subcutaneous or pulmonary metastases were selected for a study of the effectiveness of the radiosensitizer misonidazole (MIS). Evaluable data were obtained in 6 patients and radiosensitization demonstrated in 5. Patients were irradiated either before or after MIS, and each patient acted as his own control. Response to treatment in 5 cases was assessed in terms of growth delay, and radiation doses were selected in expectation of enhancement ratios of 1.2 to 1.5. In 1 case evidence of sensitization was obtained from differential tumour clearance from 2 areas of skin irradiated before or after MIS. Results in 4/5 growth-delay studies indicated enhancement ratios ranging from 1.1 to greater than 1.5. An enhancement ratio of 1.3 was measured in a case of squamous carcinoma treated by a 10-fraction course of irradiation. Evidence of sensitization was obtained in breast carcinoma, osteosarcoma, leiomyosarcoma, prostatic carcinoma and synoviosarcoma. The results of this study support the view that MIS may improve the radiotherapeutic management of a wide range of tumours, although more extensive data are required to identify those categories of disease in which greatest benefit will be obtained, and to indicate the optimum radiation schedule.
Adolescent↗
Growth kinetics of a rat mammary tumour transplanted into immune-suppressed mice.
The growth kinetics of a transplanted rat mammary tumour and its xenografts in immune-suppressed mice were studied using the technique of labelled mitoses. Growth of the tumour in rats was regular and uniform but when transplanted into mice the growth of the implants was irregular and generally slower. The second passage tumours in mice showed rapid and regular growth with a volume doubling time approximately half that for the tumours in the rat. Values for the G1 phase duration, intermitotic time and growth fraction were greater for the tumours in the mouse although the data for the first passage in mice were difficult to interpret. The kinetic changes between the rat and mouse hosts primarily reflect a large and variable amount of cell loss from the first passage xenografts in the mouse, with adaptation by the second passage towards reduced cell loss.
Animals↗
Lung damage in C57B1 mice following thoracic irradiation: enhancement by chemotherapy.
C57Bl mice were treated with thoracic irradiation to doses in the range 12.0 to 18.9 gray. Few deaths were observed in the period 80--160 days after irradiation (an end-point of lung damage used by other investigators) and the median survival times ranged from 200 to 310 days. CBA mice treated under identical conditions predominantly died between 80--160 days and it is therefore concluded that C57Bl mice show unusually prolonged survival following this treatment. Six chemotherapeutic agents were given to C57Bl mice together with thoracic irradiation, in most cases two weeks beforehand. Adriamycin, bleomycin and cyclophosphamide enhanced the mortality of the mice. Most agents had little effect on radiation-induced skin damage.
Animals↗
Human tumours in mice and rats.
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Animals↗
Influence of misonidazole on the incidence of radiation-induced intestinal tumours in mice.
C57BL mice were given local irradiation to 2 cm2 of the lower abdomen in the dose range 16--24 Gy. There were some early deaths, but mice dying between 50--240 days predominantly developed invasive adenocarcinomas of the intestine. When the radiosensitizer misonidazole was given in a single dose shortly before irradiation the proportion of mice developing tumours was higher, but the difference was not statistically significant. However, there was a significant increase in the incidence of multiple tumours, largely attributable to tumours arising in the rectum.
Adenocarcinoma↗
Improved immune-suppression techniques for the exongrafting of human tumours.
The transplantability of a xenografted human adenocarcinoma has been examined in mice that had been immune-suppressed by thymectomy and whole-body irradiation and the results have been compared with transplantation into athymic (nude) mice. Two alternative techniques were used to prevent marrow failure following whole-body irradiation: reconstituting the animals with a marrow graft, or protecting them by an injection of cytosine arabinoside (Ara-C) 2 days before the irradiation. The results show that the Ara-C-prepared mice were more receptive to transplantation than marrow-grafted or nude mice, and they were the only animals that developed regional metastases from implanted xenografts. Some recovery of immunity occurred in both types of immune-suppressed mice, which was evident more than 5 weeks after immune-suppression and which was more marked in females than in males. It was concluded that the immune-suppressed mice were superior to nude mice for short-term experiments but they may be less satisfactory for long-term experiments.
Adenocarcinoma↗
Variation in response of xenografts of colo-rectal carcinoma to chemotherapy.
Ten xenograft lines of human colonic and rectal carcinomas have been established in immune-suppressed mice. Mice bearing tumours in the 2nd to 6th passage were treated with maximum tolerated doses of 8 chemotherapeutic agents and tumour growth delay was estimated in terms of the number of volume doubling times gained by the treatment. The average response corresponded to a delay of only about 0.5 doubling times, but some tumour lines showed a good response to some agents. Twenty-three out of about 700 treated tumours failed to regrow. Statistical analysis showed no consistent difference in sensitivity among the tumour lines, but melphalan, 5-fluorouracil and hexamethylmelamine stood out as the most effective agents. A study of two-drug combinations showed that their order of administration had little effect on response. Only 4 of the patients who donated the xenografts were treated with chemotherapy, but among these there was some evidence that response in the xenografts correlated with response in the patient.
Adult↗
The proliferative state of clonogenic cells in the Lewis lung tumour after treatment with cytotoxic agents.
The proportion of clonogenic cells from the Lewis lung carcinoma which are in S-phase of the cell cycle has been measured as the fraction killed by a short exposure to hydroxyurea in vitro. Estimates of the proportions of S-phase cells before and 30 min after doses of gamma-radiation of 1000--2000 rad suggest no alternation in the cell cycle age distribution due to these doses of radiation. As the survivors of these high doses of radiation are predominantly hypoxic, the results imply that hypoxic cells have the same cell cycle age distribution as oxygenated cells in Lewis lung tumours. After treatment with cyclophosphamide or CCNU, the proportion of S-phase cells among the survivors exceeds the faction of S-phase cells in untreated populations. This increase is consistent with a relative resistance of S-phase cells to alkylating agents and nitrosoureas.
Animals↗
Influence of tumour size on radiosensitization by misonidazole.
The administration of misonidazole shortly before irradiation increased the radiation response of the Lewis lung tumour growing either as approximately 500mm3 subcutaneous implants or as 15mm3 lung colonies. In the subcutaneous tumours, the dose enhancement ratio was approximately half the oxygen enhancement ratio. In the lung colonies the sensitization of hypoxic cells appeared to be complete. Similar studies on subcutaneous B16 melanoma showed that the drug increased radiosensitivity to a level comparable with that of cells in small pulmonary nodules, whose hypoxic fraction appears to be below 10(-3). The results indicate complete dose modification of hypoxic cells where their natural proportion is small with incomplete enhancement of radiosensitivity where the natural hypoxic fraction is larger.
Animals↗
The effect of misonidazole on the radiation response of clonogenic human pancreatic carcinoma cells.
An enhancing effect of misonidazole on the in vivo radiation response of clonogenic human tumour cells from a pancreatic carcinoma xenograft has been demonstrated using both a soft agar in vitro assay and an agar in diffusion chamber assay. Enhancement ratios of 1.8 and 1.3 were found when cells were assayed at 0 h and 18 h respectively after irradiation. No enhancement was seen with in vitro irradiation of oxygenated cells. The potential of these assay systems as a perclinical screening test for new radiosensitizers is discussed.
Animals↗
The response of human tumour metastases to radiation and misonidazole.
In an attempt to investigate the radiosensitivity effect of the nitroimidazole misonidazole in man, sequential tumour volume measurements have been performed in 4 patients with metastatic malignant disease in order to compare the growth delay induced by radiation given before of 4 hours after the oral administration of the drug. One study was not completed, and there was no evidence of radiation sensitization in 2 patients. The results in the fourth patient were consistent with a small enhancement of radiation effect. Drug blood levels were followed on 9 occasions and tumour drug concentration measured in 1 patient.
Humans↗
The growth and therapeutic response of human tumours in immune deficient mice.
The development of techniques for growing human tumours in immune-deficient mice is reviewed. In a compilation of success-rates in grafting a series of types of human tumour into a variety of recipients there is evidence for different levels of success among the tumour types but little firm information on the comparative receptivity of different hosts. Adenocarcinomas, particularly of the colon, have done well, as have melanomas and some tumours of the nervous system. Breast carcinomas, squamous cell carcinomas and various sarcomas have transplanted poorly. Human tumour xenografts have been found to maintain the histological characteristics of the parent tumour and in some cases hormone production and hormone dependance have also been maintained. Evidence is accumulating on the maintainance of therapeutic sensitivity of the tumours.
Animals↗