Inhibition of Metastatic Spread by I.C.R.F. 159: Selective Deletion of a Malignant Characteristic

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: 91%

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

Sheldon¹,

Hill²

1977

“…With the Lewis lung carcinoma, the suppression of metastases by ICRF 159 is caused by failure of tumour cells to enter the blood from the initial tumour graft, since no circulating malignant cells are found in drug treated mice, in comparison with untreated animals (Salsbury et al, 1970). In the present studies, however, chemotherapy with ICRF 159 in conjunction with surgical excision of epithelioma Sp 1 grafts failed to restrict the development of pulmonary metastases.…”

Section: Icrf 159contrasting

confidence: 55%

mentioning

confidence: 99%

“…Althouigh a powerful anti-mitotic (Sandberg and Goldin, 1971) (Salsbury et al, 1970;Le Serve and Hellmann, 1972). The presence in ICRF 159 treated animals of a well formed vasculature between tumour cells and blood has been interpreted as the main factor in preventing haematogenous tumour spread (Salsbury et al, 1970;Hellmann et al, 1973). The clinical application of ICRF 159 to the treatment of acute leukaemia and lymphosarcoma has been described (Hellmann et al, 1969), although the beneficial effects reported in these cases were interpreted as due to the drug's anti-mitotic action.…”

mentioning

confidence: 99%

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Influence of ICRF 159 and triton WR 1339 on metastases of a rat epithelioma

Pimm¹,

Baldwin²

1975

Summary.-ICRF 159 and Triton WR 1339 have been examined for their ability to suppress subcutaneous growth and pulmonary metastases from a transplanted rat epithelioma. Neither compound influenced subcutaneous tumour development or reduced the propensity to metastasize when administered in regimens reported to suppress pulmonary, lymph node or intracerebral metastases in other experimental systems.

“…The Lewis lung carcinoma in C57BL mice has been chosen as a suitable model; it arose spontaneously in this strain (Sigiura and Stock, 1955) and has been maintained strictly in the same strain. After s.c. inoculation in the flank, it grows as a local solid tumour and metastasizes to the lungs consistently in the third week (Salsbury, Burrage and Hellmann, 1970). In our experience, increased resistance to the tumour has not been shown to follow immunization of syngeneic recipients, and we know of no examples of spontaneous regression.…”

mentioning

confidence: 99%

Alterations of mononuclear phagocyte function induced by Lewis lung carcinoma in C57BL mice

Otu¹,

Russell²,

Wilkinson³

et al. 1977

Summary.-The function of the reticulo-endothelial system in mice bearing Lewis lung carcinomas has been measured by (1) the rate of clearance of carbon particles from the circulation in vivo and calculation of the phagocytic index K; (2) chemotactic locomotion of macrophages in vitro in the presence or absence of serum or tumour supernate. The ability of the bone marrow to develop macrophage colonies in vitro in the presence or absence of sera from tumour-bearing mice has also been tested.A clear depression of macrophage locomotion and macrophage colony formation in vitro was found in the presence of sera or tumour supernates from tumour-bearing mice as early as 24 to 72 h after tumour inoculation. Similarly, tumour-bearing mice showed marked depression of carbon clearance in tests repeated throughout the first 72 h after tumour inoculation. This early depression of macrophage function may be an important step in allowing escape of tumour cells from host resistance.