Studies on the toxicity of the antitumour agent N-methylformamide in mice.

Aspects of the toxicology of N-methylformamide (NMF), an investigational antitumour agent, were studied in mice. After injection of NMF at its LD10 (800 mg/kg) dosage the total peripheral white blood cell and platelet counts were unchanged in BALB/c mice. A mild granulocytosis was seen in this strain after administration of the LD50 (2300 mg/kg) dosage.

Interaction of the antibiotic adriamycin with the plasma membrane.

The antitumor antibiotic adriamycin was found to be a potent modulator of the human erythrocyte discocyte echinocyte transition. Incubation of discocytes for 10 min with 10 microM adriamycin inhibited calcium-induced echinocytosis by 90 per cent. Adriamycin itself had no effect on erythrocyte morphology, a feature which distinguished it from other amphipaths which bring about the formation of a cupped cell morphology.

Calcium-induced heterogeneous changes in membrane potential detected by flow cytofluorimetry.

Ionophore-induced changes in the cell-associated fluorescence of samples of approx. 50000 individual murine L1210 leukemia cells which had been incubated with the voltage-sensitive dye 3,3'-dihexyloctacarbocyanine iodide (DiOC6(3] were monitored by flow cytometry. The K+ ionophore valinomycin (1 microM) produced homogeneous changes in the fluorescence of the entire population, the magnitude of which was dependent upon the concentration of extracellular K+.

Culpability and accountability of hospitalized injured alcohol-impaired drivers. A prospective study.

During the three-year period ending October 1982, driver records, crash reports, and blood alcohol concentrations were correlated for 56 alcohol-impaired drivers injured seriously enough to warrant hospital admission. Blood alcohol concentration levels exceeded 0.15 vol% in all patients.

Results of treatment of subchondral bone cysts in the medial condyle of the equine femur with an autogenous cancellous bone graft.

The results of surgical treatment of 10 subchondral bone cysts, all located in the medial femoral condyle, are presented. A cancellous bone graft was used in nine cases and a two component acrylic bone cement was used in the case of an extremely large cyst. Eight out of the 10 cases made a satisfactory clinical recovery.

A 45-kb DNA domain with two divergently orientated genes is the unit of organisation of the murine major urinary protein genes.

The multigene family which codes for the mouse major urinary proteins (MUPs) consists of approximately 35 genes. Most of these are members of two different groups, Group 1 and Group 2, which can be distinguished by nucleic acid hybridisation. By screening a Charon 4A library of mouse DNA with probes from the 5'-flanking region of a MUP gene, we have isolated clones that contain both a Group 1 and a Group 2 gene, orientated in a divergent fashion, with 15 kb of DNA between the 5' ends of the genes.

DNA cross-linking and cytotoxicity in normal and transformed human cells treated in vitro with 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d] -1,2,3,5-tetrazin-4(3H)-one.

Normal (IMR-90) and SV40-transformed (VA-13) human embryo cells were treated with 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d] -1,2,3,5-tetrazin-4(3H)-one (M&B 39565), and the effects of the drug on cell viability and cellular DNA integrity were studied. The effects of M&B 39565 were compared with one of its potential decomposition products 5-[3-(2-chloroethyl)triazen-1 -yl]imidazole-4-carboxamide (MCTIC). M&B 39565 and MCTIC were 5- to 6-fold more toxic to VA-13 cells than to IMR-90 cells for drug concentrations which produced a 2-log cell kill, as measured by colony-forming assays.

Effects of the antitumor agent 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one on the DNA of mouse L1210 cells.

L1210 murine leukemia cells were treated in vitro with the novel antineoplastic agent 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d] -1,2,3,5-tetrazin-4(3H)-one (M&B 39565), and its interaction with cellular DNA was assessed by alkaline elution. DNA interstrand cross-link and DNA-protein cross-link formation was quantified with regard to drug concentration and length of incubation time after a 2-hr incubation period with drug. Cytotoxicity, as measured by colony formation assays, and DNA damage caused by M&B 39565 were compared with those caused by a breakdown product of M&B 39565, 5-[3-(2-chloroethyl)triazen -1-yl]imidazole-4-carboxamide (MCTIC) and also with 1-(2-chloroethyl)-1-nitrosourea (CNU).

The chemosensitivity of a new experimental model--the M5076 reticulum cell sarcoma.

The M5076 reticulum cell sarcoma is a murine tumour of potential value in experimental chemotherapy. Experiments were conducted to ascertain the growth characteristics and chemosensitivity of this neoplasm in the BDF1 mouse. The intramuscular tumour proved to be responsive to the alkylating agents, nitrosoureas, procarbazine, DTIC and treosulphan, yet insensitive to the antimetabolites and only weakly responsive to adriamycin.

Discriminant value of clinical and exercise variables in detecting significant coronary artery disease in asymptomatic men.

To determine whether clinical or exercise test variables could reliably detect coronary disease in asymptomatic men, several variables were compared with angiographic findings in 225 asymptomatic men. None of the individual clinical or rest electrocardiographic variables were able to detect coronary artery disease. The three individual exercise variables with a high likelihood ratio were: 1) at least 0.

Angiographic diagnosis of posterior mitral valve leaflet prolapse.

The left ventricular cineangiograms of 22 asymptomatic, apparently healthy male aviators without noninvasive (echocardiographic or auscultatory) evidence of mitral valve prolapse were reviewed and compared with those of 12 men with noninvasive evidence of mild mitral valve prolapse. The maximal protrusion of the posterior mitral valve leaflet superior and posterior to a line perpendicular to the long axis of the left ventricle at end-systole was measured from the right anterior oblique left ventricular cineangiogram by repeated observation of left ventricular inflow. The values were 7.

Studies of the mode of action of antitumor triazenes and triazines. 6. 1-Aryl-3-(hydroxymethyl)-3-methyltriazenes: synthesis, chemistry, and antitumor properties.

1-Aryl-3-(hydroxymethyl)-3-alkyltriazenes [ArN = NN(CH3)CH2OH] have been synthesized by diazonium coupling to the carbinolamine (RNHCH2OH), generated in situ from the alkylamine and formaldehyde mixtures. The (hydroxymethyl)triazene structure has been confirmed by IR, NMR, and mass spectral analysis and also by the preparation of a crystalline benzoate derivative. The mass spectra of the (hydroxymethyl)triazenes suggest that they fragment by loss of formaldehyde to give the methyltriazene, which is also the product of hydrolysis in solution.

Limitation of exercise-induced R wave amplitude changes in detecting coronary artery disease in asymptomatic men.

The exercise electrocardiograms of 255 asymptomatic men were analyzed for changes in R wave amplitude and ST segments. The results were correlated with findings at cardiac catheterization. There were 65 men with coronary artery disease and 190 normal subjects.

Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent.

Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-on es. In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively. Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.

The formation and metabolism of N-hydroxymethyl compounds--IV. Cytotoxicity and antitumour activity of N-hydroxymethylformamide, a putative metabolite of N-methylformamide (NSC 3051).

Experiments were conducted to test the hypothesis that N-hydroxymethylformamide (HMF) is the active metabolite of the antitumour agent N-methylformamide (NMF). In an in vitro bioassay against the TLX5 lymphoma HMF was more cytotoxic than NMF; this cytotoxicity was abolished by preincubating the TLX5 cells with semicarbazide, a formaldehyde trapping agent. Similarly, the inhibition of incorporation of radiolabelled thymidine, uridine, formate and leucine into TLX5 cells elicited by HMF was eliminated by preincubation of the cells with semicarbazide.

Use of an autogenous cancellous bone graft in the treatment of subchondral bone cysts in the medial femoral condyle of the horse.

The clinical features, diagnosis and radiological findings of eight cases of a subchondral bone cyst involving the medial condyle of the femur are described. Surgical treatment, which comprised performing an arthrotomy of the femorotibial joint, curetting and packing the cystic cavity with an autogenous cancellous bone graft, is described.

Pyoderma gangrenosum.

Since its description 50 years ago, pyoderma gangrenosum has continued to capture the attention and imagination of all those who see its dramatic presentation. Clinical observation still provides the only reliable diagnosis. As investigative techniques increase, more and more intriguing immunologic abnormalities associated with this disorder are discovered, but understanding of the pathogenesis remains elusive.

The formation and metabolism of N-hydroxymethyl compounds--III. The metabolic conversion of N-methyl and N,N,-dimethylbenzamides to N-hydroxymethyl compounds.

The stability of metabolically-generated N-(hydroxymethyl) compounds was investigated using a series of N-methylbenzamides as model substrates. N-(Hydroxymethyl)-benzamide was characterized as a major metabolite of N-methylbenzamide in vitro, and was also identified as a urinary metabolite of N-methylbenzamide. N-(Hydroxymethyl) compounds were also found as metabolites of 4-chloro-N-methylbenzamide and 4-t-butyl-N-methylbenzamide in vitro.