Abstract
Clonogenic growth (colony-forming efficiency, CFE) of i.v. injected allogeneic W256 tumour cells in the lungs was markedly enhanced by treatment of rats with alpha-naphthyl thiourea (ANTU) injected i.p. from 2 h before to 2 h after the tumour cells. ANTU specifically increases pulmonary vascular permeability in adult rats and causes acute pulmonary oedema and pleural effusion. Inhibition of drug toxicity to the lungs by tachyphylaxis, specific antimetabolites or iodides did not abolish the effect of ANTU on CFE. CFE was not increased when cells were seeded by i.v. injection the lungs affected by advanced pulmonary oedema at 6 to 24 h after treatment with drug. ANTU did not enhance growth of intratracheally injected cells. Although ANTU has no cytotoxic or immunosuppressive action, treatment of tumour-immunized rats with ANTU caused apparent "breakdown" of tumour immunity in 50% of rats, by causing growth of tumour colonies in the lungs. Possible mechanisms for the ANTU-induced decrease in innate resistance to growth of tumour in the lungs are discussed.
Highlights
ac-naphthyl thiourea (ANTU) has no cytotoxic or immunosuppressive action, treatment of tumour-immunized rats with ANTU caused apparent "breakdown" of tumour immunity in 50% of rats, by causing growth of tumour colonies in the lungs
In order to test this concept, we have studied the effects on tumour CFE in the lungs of treatment of rats with the rodenticide, ac-naphthyl thiourea (ANTU), a compound which induces acute pulmonary oedema and pleural effusion (Richter, 1945) but has no significant effects on blood vessels and vascular permeability in other organs (Richter, 1952; Cunningham and Hurley, 1972)
Older rats could be made highly resistant to the toxic effects of ANTU on the lungs by (1) tachyphylaxis, induced by injecting rats with small doses of ANTU for a few days before challenge with larger doses of 5 mg/kg or more, (2) pretreatment for 4-5 days with iodine or KI added to their drinking water, (3) combined injection of ANTU with I-ethyl-l-phenyl-2thiourea (EPTU) or propyl thiouracil (PTU) which act as specific antimetabolites in antagonizing the toxicity of ANTU and related toxic thioureas to the lungs
Summary
Tumour CFE in ANTU-treated rats (1) Toxicity of ANTU.-I.p. injection of grown rats, aged 6 weeks or more, with 5 mg ANTU/kg body wt caused acute pulmonary oedema and pleural effusion to appear 2-3 h after injection; the oedema rapidly increased and reached maximum intensity at about 4-5 h, and thereafter over the 24-48 h it resolved slowly but completely (van den Brenk et al, 1976b; see Fig. 1). It was found that over 90% of such older rats given 5 mg/kg survived, but that death usually occurred within 8 h when the dose was increased to 10 mg ANTU/kg. A smaller dose of 2 mg ANTU/kg rarely caused pulmonary oedema and pleural effusion. In young (3to 4-week-old) rats, doses of 10-100 mg ANTU/kg failed to cause pulmonary oedema, but subsequently toxicity to the won_300.
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