A study of the influence of various diagnostic and therapeutic procedures applied to a murine squamous carcinoma on its metastatic behaviour

Summary.-Tumour experiments including local control after X-irradiation have been performed, using a new technique that eliminates the need for anaesthetics in restraining the animals. This system has been used to investigate the degree of sensitization that can be achieved with ICRF 159 and 4 strongly electron-affinic radiosensitizers, nifurpipone dihydrochloride, metronidazole, Ro-11-3696 and Ro-07-0582.No significant enhancement of the radiation effect was observed with ICRF 159. Significant sensitization was achieved by all 4 nitro-heterocyclic compounds, Ro-07-0582 being the most effective, metronidazole and Ro-11-3696 the next, and nifurpipone dihydrochloride the least effective.For Ro-07-0582 and metronidazole, several drug concentrations were investigated, and the interval between injection with Ro-07-0582 and irradiation was varied: an interval of 30 min gave more sensitization than an interval of 90 min.The results from the local control experiments using Ro-07-0582 have been compared with those obtained from regrowth delay experiments. The radiosensitization obtained by the Ro-07-0582 increased with the X-ray dose above 25 gray.Both metronidazole and Ro-07-0582 gave significant enhancement of effect at serum concentrations which can be achieved in man.

Section: Discussionsupporting

confidence: 90%

Hypoxic cell radiosensitizers and local control by X-ray of a transplanted tumour in mice

Sheldon¹,

Hill²

1977

“…Evidence of the non-immunogenicity of these tumours appears elsewhere (Peters, 1975;Hewitt, Blake and Walder, 1976). CBA Carcinoma NT has featured in several previous experimental studies Hewitt, Blake and Porter, 1973;Peters and Hewitt, 1974).…”

Section: Methodsmentioning

confidence: 91%

Further studies of the relationship between lymphatic dissemination and lymphnodal metastasis in non-immunogenic murine tumours

Hewitt¹,

Blake²

1977

Summary.-In all 6 different murine tumours of spontaneous origin, a high proportion (22-95%) of the regional lymph nodes draining small intradermal tumours gave rise to tumours after their isogeneic transplantation as whole nodes. In separate experiments with 4 of these tumours, equivalent tumour-bearing mice had their tumours surgically excised and were observed for the development of regional nodal metastasis: in all 4, the incidence of nodal metastasis was significantly less than the corresponding frequency of tumour formation by transplanted nodes. After high-dose radiotherapy of intradermal carcinomas, there was a progressive fall in the incidence of positive regional node transplants from 48 to 96 h after irradiation. It is concluded that continual lymphatic dissemination of viable cancer cells is characteristic of malignant tumours, but that there is a relatively small chance of such cells giving rise to nodal metastatic growth.Related studies showed that the ability of a small number of cancer cells to give rise to tumours was very much greater if they were incorporated in a lymph node at transplantation than if they were transplanted directly as a suspension. WE reported previously (Hewitt andBlake, 1975) that -.-' 40% of regional nodes draining intradermal grafts of WHT Squamous Carcinoma " D " contained viable tumour cells (as demonstrated by their giving rise to tumours after their isogeneic transplantation), whereas only 4% of regional nodes gave rise to metastasis if left in situ in mice whose tumours were excised. Since the proportion of nodes which gave rise to tumours on transplantation did not significantly increase with increase in size of the tumours drained, we concluded that a continual stream of tumour cells passes through the node during tumour growth, and that these cells have only a low potential for seeding in the nodes. We report here further related studies which allow (i) extension of our conclusions to a wider range of tumours; (ii) an assessment of the efficiency of whole-node transplantation as a means of detecting a small content of tumour cells; and (iii) an indication of the time taken for tumour cells to be cleared from the lymph node after ablation by surgery or irradiation of the tumour drained. By using non-immunogenic tumours of spontaneous origin and by confining our attention to natural dissemination of cells, we believe we have represented clinical phenomena more faithfully than can be achieved by the more common use of induced immunogenic tumours disseminated artificially by intralymphatic or intravascular injection of a dense bolus of cells. MATERIALS AND METHODSMice.-Female mice of inbred strains WHT/Ht and CBA/Ht, bred in this laboratory, were used at 2-4 months of age.Tumours.-All 6 of the tumours used

“…The experimental system, consisting of a spontaneously arising syngeneically transplanted murine squamous carcinoma, has been described in detail in the preceding paper (Peters, 1975). A series of experiments was there reported which tested the influence of various diagnostic and therapeutic procedures applied to the primary tumour implant on the subsequent development of metastases.…”

Section: Aiaterials and Methodsmentioning

confidence: 99%

The natural history of metastasis of a syngeneic murine squamous carcinoma and the prognostic implications of primary tumour size and duration of growth

Peters¹

1975

Self Cite

Summary.-A study has been made of the natural history of metastasis of a spontaneous murine squamous carcinoma implanted into syngeneic recipients-a situation where biologically different tumours and variable " host resistance " are not complicating issues. The time distribution of deaths from metastatic disease was incompatible with a log-normal distribution but was accurately described by an exponential pattern of survival following an initial lag. While the average life of doomed mice correlated with predictions based on growth rates, there was a wide range of survival times indicating random influences on the evolution of metastatic disease.Insofar as tumours which grew to 20 mm3 or less in 5 days after tumour cell injection failed to initiate metastases, while tumours which reached a size of 120 mm3 or greater (irrespective of duration) produced metastases in 38/39 mice, tumour size was a prognostic index. However, within the size range 33-150 mm3 the correlation between metastatic risk and size was not statistically significant. No correlation between metastatic risk and duration of tumour growth from 6 to 29 days was observed. Two integral functions of tumour size and duration were tested but neither gave a better correlation with metastatic risk than did size alone.