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Biomedical subjects

M A Knowles

Publications and source records attributed to M A Knowles.

78 records · Page 5Linked to original sources

Effects of the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate on normal and "preneoplastic" mouse submandibular gland epithelial cells in vitro.

The effect of the promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) was studied on mixed primary cultures of C57BL/Icrf-at mouse submandibular gland and on slowly proliferating preneoplastic epithelial foci derived from such cultures. No cytologic alterations were noted in the TPA-treated epithelium. The development of three-dimensional epithelial ducts occurring between 30 and 60 days in vitro in untreated cultures was markedly inhibited in TPA-treated cultures. Epithelial proliferation, as shown by the [H]thymidine labelling index and mitotic index, seemded to increase during treatment with TPA and fall between the weekly treatments. Long-term TPA treatment increased the incidence of slow-growing foci in cultures previously treated with 7,12-dimethylbenz[a]anthracene but not in cultures treated with dimethyl sulfoxide. TPA had no effect on the emergence of tumorigenic cell lines at a late stage in culture or on the development of such lines from preexisting foci derived from non-TPA-treated cultures.

9,10-Dimethyl-1,2-benzanthracene↗

The structure of tumours derived from mouse submandibular gland epithelium transformed in vitro.

The morphology and ultrastructure of 48 primary tumours established from 5 cell lines of adult mouse salivary gland epithelial cells transformed in vitro are described. Tumours from 4 of the cells lines were adenocarcinomas with a wide range of structural variation, and resembled human salivary gland carcinomas. The fifth cell line produced tumours with carcinomatous and sarcomatous elements.

Animals↗

Ultrastructure and biological markers of neoplastic change in adult mouse epithelial cells transformed in vitro.

The ultrastructure and in vitro growth properties of 5 tumorigenic mouse submandibular-gland epithelial cell lines were studied. In all lines, in vitro acinus formation occurred, and well differentiated epithelial cells showing epithelial microvilli and desmosomes and cytoplasmic tonofilaments were present. None of the cells showed specific ultratructural features of the normal differentiated submandibular-gland ducts. All the lines formed colonies in semi-solid agar and on confluent monolayers of BALB/c 3T3 cells, and all lacked density-dependent inhibition of growth, as demonstrated by a random distribution of [3H]TdR labelling throughout growing colonies. These 3 growth properties appear to be reliable in vitro markers for epithelial neoplastic transformation in this system, but colony-forming efficiency in agar is lower than that reported for many transformed mesenchymal cells.

Animals↗

Stages in neoplastic transformation of adult epithelial cells by 7,12-dimethylbenz(a)anthracene in vitro.

Five tumor-producing cell lines were established from explant cultures of adult C57BL mouse submandibular gland. Four lines were from cultures treated for 24 hr on Day 4 of culture with 7,12-dimethylbenz(a)anthracene. Three of these gave rise to adenocarcinomas after transplantation into syngeneic mice; the fourth produced tumors with carcinomatous and sarcomatous areas. The fifth cell line was derived from an untreated culture and gave rise to adenocarcinomas. A series of four well-defined morphological stages occurred in the cultures before tumor-producing cell lines were established. In Stage I (0 to 30 days) there was an outgrowth of epithelium; in Stage II (30 to 70 days) ductal differentiation occurred in some epithelium; in Stage III (70 to 100 days) small, slowly proliferating foci developed either from the ducts or from flat epithelial areas. In Stage IV (over 100 days) the proliferation rate in some of the foci increased, and the cells became more irregular. The cells could not be transferred easily until about 150 days, after which time they were tumor producing. Neoplastic transformation occurred between 158 and 240 days in the treated cultures and at 325 days in the untreated culture.

9,10-Dimethyl-1,2-benzanthracene↗

Anticonvulsant properties of calcium channel blockers in mice: N-methyl-D-,L-aspartate- and Bay K 8644-induced convulsions are potently blocked by the dihydropyridines.

Ten calcium channel blockers were evaluated in mice after intraperitoneal (i.p.) administration for prevention of seizures induced by various convulsants. The dihydropyridines (class II calcium antagonists, i.e., nisoldipine, nitrendipine, nicardipine, nifedipine, and nimodipine) selectively prevented seizures elicited by administration of pentylenetetrazol (PTZ), N-methyl-D,L-aspartate (NMDLA) and the dihydropyridine calcium channel agonist BAY K 8644. With regard to prevention of NMDLA-induced seizures and the subsequent mortality, these compounds were similar in potency to the noncompetitive NMDA receptor antagonist MK801. Unlike MK801 (IC50 = 0.014 microM), the dihydropyridines did not inhibit in vitro binding of MK801 to synaptic membrane fractions prepared from rat cerebrohippocampal tissue. The dihydropyridines did not influence seizures elicited by maximal electroshock (MES). Flunarizine (diphenyl-alkylamine, class IV) was selectively active in the MES test, considerably less potent against NMDLA-induced convulsions/mortality, exhibited weak noncompetitive NMDA antagonism in vitro (IC50 = 28 microM), and was inactive in the PTZ and BAY K 8644 testing paradigms. Diltiazem, a class III benzothiazepine, possessed relatively weak broad spectra of activity against MES, PTZ, NMDLA, and BAY K 8644 test situations. It was inactive in vitro as a noncompetitive NMDA antagonist. The class I compound verapamil (phenylalkylamine) displayed only moderate inhibition of NMDLA-evoked seizures/mortality. Prenylamine (class V) was moderately active against convulsions produced by MES and NMDLA while retaining a degree (IC50 = 16 microM) of noncompetitive NMDA antagonism. Lidoflazine (class VI) was inactive in all tests. The Ca2+ channel blockers and MK801 were inconsistent in their ability to prevent bicuculline (BIC)-elicited convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗