thiourea and Carcinoma-256--Walker

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.

Topics: Adrenalectomy; Animals; Carcinoma 256, Walker; Clone Cells; Dose-Response Relationship, Drug; Female; Injections; Lung Neoplasms; Neoplasm Transplantation; Pleural Effusion; Pulmonary Edema; Rats; Tachyphylaxis; Thiourea; Thyroidectomy; Time Factors

In order to assess the role played respectively by the pseudothiourea group and the alkylic chain in the inhibition of protein synthesis and tumour growth caused by compound AHR-1911, a series of eight related substances were studied. The blockade of protein synthesis on liver and Walker carcinoma ribosomes and on suspensions of Walker carcinoma cells, depended essentially on the length of the alkylic chain and the substitution in C-1. The minimum chain was 9 carbons and a plateau in the activity was reached at 11 carbons. Replacement of the thiourea group in C-1 by an NH2 group did not change the pattern. A double bond in the distal section of the chain (AHR-1911) increased inhibition on intact cells with a parallel decrease in cytotoxicity, and reduced the aggregation of ribosomes, protein synthesis factors and other proteins. The antitumor effect depends on the pseudothiourea group and is not caused primarily by interference with protein synthesis. Aminoacyl tRNA binding and transfer appeared to be targets of AH4-1911, but this did not affect significantly tRNA change or nascent peptide release. Drug binding to ribosomes and their subsequent aggregation can be regulated by K+ concentration and temperature. It is assumed that the inhibition of protein synthesis is caused by AHR-1911 effects on elongation factors, impairing their interaction with ribosomes.

Topics: Animals; Carcinoma 256, Walker; In Vitro Techniques; Isothiuronium; Leukemia L1210; Liver; Male; Mice; Mice, Inbred DBA; Neoplasm Proteins; Protein Biosynthesis; Puromycin; Rats; Ribosomes; RNA, Neoplasm; RNA, Transfer; Structure-Activity Relationship; Thiourea

A new thiopseudourea, S-(10-undecen-1-yl)isothiouronium iodide (compound AHR-1911), was tested for antitumour action and shown to inhibit considerably the growth of the Walker carcinoma in rats. The mechanism of its effect on protein and nucleic acid synthesis was then studied with systems in vitro from rat liver. In incubations of liver slices, 1.4mm-compound AHR-1911 decreased by 96% the incorporation of [(14)C]leucine into microsomal proteins, and mitochondrial protein synthesis measured in the presence of cycloheximide was decreased by 44%. At lower doses, translation, as well as the incorporation of [(3)H]uridine into RNA, was also considerably impaired, compound AHR-1911 being the most active of all the thiopseudoureas tested whereas undecylenic acid and thiourea by themselves showed practically no inhibition. Protein synthesis by cytoplasmic ribosomes (microsomes and C-polyribosomes) was inhibited by compound AHR-1911 at different concentrations (72% at 0.42mm), and again the other related compounds were much less effective, with the exception of one antileukaemic thiopseudourea. The same occurred with the poly(U)-stimulated incorporation of phenylalanine. The puromycin reaction with pulse-labelled C-ribosomes was strongly inhibited, particularly when preincubation with compound AHR-1911 preceded the addition of puromycin, with no release of nascent chains by the thiopseudourea alone. In the presence of GTP and pH5 fraction, to induce translocation and transform all the ribosomes to the donor state, the percentage inhibition remained the same. The ribosomes incubated with the drug are aggregated, as shown by the polyribosome profile, but, when excess of inhibitor was removed, the activity in protein synthesis and the puromycin reaction was restored, indicating that the inhibition is not due to the polyribosomal aggregation. These results suggest that the effect on translation with both 55S and 80S ribosomes is derived from inhibition of chain elongation at the level of transpeptidation and not translocation, probably together with the interference with transcription playing a role in the antitumour activity.

Topics: Animals; Carbon Radioisotopes; Carcinoma 256, Walker; Centrifugation, Density Gradient; Cycloheximide; In Vitro Techniques; Leucine; Liver; Male; Polyribosomes; Protein Biosynthesis; Rats; RNA; Thiourea; Transcription, Genetic; Tritium; Undecylenic Acids; Uridine

Topics: Animals; Antineoplastic Agents; Carcinoma; Carcinoma 256, Walker; Carcinoma, Ehrlich Tumor; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Liver Neoplasms; Lymphoma, Non-Hodgkin; Male; Melanoma; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Osteosarcoma; Rats; Sarcoma, Experimental; Thiourea; Urea