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Biomedical subjects

J S Lazo

Publications and source records attributed to J S Lazo.

160 records · Page 9Linked to original sources
PubMed1983

Pulmonary endothelial dysfunction in the presence or absence of interstitial injury induced by intratracheally injected bleomycin in rabbits.

Previously, we reported that repeated subcutaneous administration of bleomycin (BLM) to rabbits produced functional and structural endothelial damage with no evidence of interstitial fibrosis. In the present study, rabbits received intratracheally a single injection of BLM (6 units/kg, n = 6: "low dose" or 11 units/kg, n = 4: "high dose"); 6 additional animals received intratracheally an injection of saline and served as controls. Four weeks after BLM administration, the low-dose group demonstrated significant reduction in the single-pass pulmonary removal of 14C-5-hydroxytryptamine (5-HT) (p less than 0.05; n = 4), whereas 3H-norepinephrine (NE) removal and 3H-benzoyl-phe-ala-pro (BPAP) substrate for lung angiotensin converting enzyme (ACE) metabolism in vivo, as well as lung and serum ACE activity in vitro remained at control levels. No morphologic or biochemical evidence of fibrosis was observed. In contrast, the high-dose BLM group exhibited significant reductions in 14C-5-HT and 3H-NE removal and 3H-BPAP metabolism in vivo, but no significant changes in lung or serum ACE activity in vitro. Furthermore, there was evidence of fibrosis, as revealed by a 59% increase in lung hydroxyproline content and by light microscopic examination of lung tissue. We conclude that intratracheal administration of BLM to rabbits can produce endothelial dysfunction in the presence or absence of interstitial injury.

Animals↗
PubMed1982

Solubilization of murine melanoma xylosyltransferase and galactosyltransferase activities and their inactivation by dialdehyde nucleosides.

The enzymes involved in the initial steps in the biosynthesis of glycosaminoglycans were examined in the murine B16 melanoma. Approximately 60% of the melanoma xylosyltransferase activity and nearly all of the galactosyltransferase activity were membrane-bound; these enzymatic activities were solubilized by treatment with Nonidet P-40 and potassium chloride, and the Michaelis constants for the substrates and acceptor molecules were determined and found to be comparable to those reported for these enzymes from the chick embryo and a rat chondrosarcoma. Dialdehyde nucleosides, which have been reported to alter the activity of several enzymes involved in nucleic acid synthesis, inhibited both xylosyltransferase and galactosyltransferase activities, with galactosyltransferase being considerably less sensitive than xylosyltransferase. The inhibition of xylosyltransferase by dialdehyde nucleosides was irreversible, with no apparent specificity for the base moiety of the dialdehyde nucleosides.

Adenosine↗
PubMed1982

Bleomycin hydrolase activity and cytotoxicity in human tumors.

A sensitive new method to assay bleomycin (BLM) metabolism was developed using an ion-paired, reverse-phase high-pressure liquid chromatography technique in conjunction with fluorescence detection that allowed levels of BLM less than 20 ng/ml to be detected. The metabolism of bleomycin B2 in homogenates from benign and malignant human tumors was studied, and all 14 tumors were capable of metabolizing bleomycin to desamidobleomycin B2. Metabolites other than desamidobleomycin B2 were not detected. BLM hydrolase activities in individual tumors varied more than 7-fold. The importance of BLM hydrolase in limiting the therapeutic effectiveness of BLM was examined by measuring BLM hydrolase activity and response of human tumors to BLM in culture. Response to BLM in culture was measured by dissociating human tumors to form single-cell suspensions and exposing the cells to 0.05 or 1 microgram/ml of BLM for 1 hr. Colony formation after BLM treatment was determined in soft agar and when compared to that of untreated cells, varied by more than 100-fold. No correlation was observed, however, between BLM hydrolase activity and response to BLM in soft agar. Thus, human tumors can metabolize BLM, and while BLM hydrolase activity may be important in tumor resistance to the drug, these data suggest that either (a) the enzyme activity in the tumor homogenate does not reflect that in the clonogenic cells or (b) other mechanisms of resistance may be operative.

Bleomycin↗
PubMed1981

Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells.

The cytotoxicities of a number of antineoplastic agents to oxygenated and hypoxic EMT6 mouse mammary tumor cells in culture were examined. Based on the relative sensitivities of cells under aerobic and hypoxic conditions, drugs were placed into three categories. Drugs that were preferentially toxic to cells under oxygenated conditions were classified as type 1 agents; this group includes bleomycin, procarbazine, streptonigrin, actinomycin D, and vincristine. Type 2 agents were those preferentially toxic to cells under hypoxic conditions. These include mitomycin C and Adriamycin. On the basis of other published reports, the glucose analogs, 5-thio-D-glucose and 2-deoxy-D-glucose, and the radiosensitizers, misonidazole and metronidazole, can also be placed in this category. Several antineoplastic agents showed no major preferential toxicity to cells under the conditions of oxygenation or hypoxia used in these experiments and were placed in a third class. This group (type 3) includes 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cis-diamminedichloroplatinum(II), 5-fluorouracil, and methotrexate. The success of many combination chemotherapy and combined modality treatments may be due to their ability to kill both the hypoxic and aerobic cell populations of solid tumors. Future chemotherapeutic regimens for the treatment of solid tumors should include agents and modalities directed toward the hypoxic cell population of the tumor, as well as toward the proliferating and nonproliferating tumor cell compartments; a therapeutic approach to the selection of antineoplastic agents for use in combination based upon physiological considerations of the architecture of solid tumors is presented.

Animals↗
PubMedDate not supplied

Aromatase activity in human ovarian cancer.

Eighty-four tumor samples from 70 women with primary ovarian cancer were assayed for cytosol estrogen (ERc) and progestin (PRc) receptor concentrations and aromatase activity. In addition, 22 of the tumors were studied for their response to the aromatase inhibitor, 4-OH-androstenedione, in a soft agar clonogenic cell assay system. Although aromatase activity was detected in almost all of the primary tumors, this enzyme was barely detectable in the majority of metastatic tumor samples. There was no significant correlation between aromatase activity and either the ERc or PRc content of the tumors, or tumor grade. Of 12 tumors grown successfully in the soft agar culture system, only 1 showed a substantial (greater than 50%) reduction in colony-forming efficiency after exposure to the aromatase inhibitor. These results suggest that local estrogen biosynthesis probably does not play an important role in the majority of epithelial ovarian tumors. However, there may be a small subset of estrogen receptor-positive tumors in which aromatase could provide a local growth stimulus.

Androstenedione↗
PubMedDate not supplied

Effect of anti-calmodulin drugs on the growth and sensitivity of C6 rat glioma cells to bleomycin.

Antipsychotic drugs that bind to and inhibit the action of calmodulin also inhibit cellular proliferation. In addition these drugs are cytotoxic to most malignant cells and can augment the antiproliferative and cytotoxic effects of bleomycin. They are attractive candidates for use against tumors of the central nervous system since they readily pass the blood-brain barrier and accumulate in the brain. To identify more active derivatives, we studied the effect of a series of phenothiazines and a group of related compounds alone or in combination with bleomycin against rat glioblastoma cell lines. C6 cells were grown for 24 hours prior to a 48 hour exposure to anti-psychotic drug alone or to an IC20 concentration of antipsychotic drug with bleomycin. Cells were stained with methylene blue and enumerated spectrophotometrically. Eight phenothiazines were found to augment the effect of bleomycin by > or = 3-fold. These included 1-chlorpromazine (3.8x), chlorpromazine (3.2x), 3-chlorpromazine (3.0x), 4-chlorpromazine (3.4x), thiomethylpromazine (3.3x), didesmethylchlorpromazine (11x), fluphenazine (5.5x) and trifluoperazine (3.2x). Structurally similar compounds also having activity included trans-flupenthixol (6.0x), 2-chloroimipramine (6.0x), desipramine (22x), and penfluridol (24x). There was a direct correlation between the antiproliferative effect of anticalmodulin compounds and the ability of these drugs to inhibit the activation of calmodulin-sensitive phosphodiesterase. However, there was no correlation between the inhibition of calmodulin and the augmentation of the antiproliferative activity of bleomycin. Penfluridol, one of the most active compounds, was chosen for further study. It increased the activity of bleomycin against L1210 leukemic cells by 90-fold and MCF-7 human breast cancer cells by 4-fold. The effect of penfluridol in combination with bleomycin was due to increased cytotoxicity as measured by clonogenic assay.

Animals↗
PubMedDate not supplied

Efficient lipofection with cisplatin-resistant human tumor cells.

Seven of seven different cisplatin-resistant human tumor cell lines showed elevated lipofection activity as compared with their sensitive parent cells, although the degree of enhancement was not quantitatively correlated with the degree of cisplatin resistance. Enhanced transfection was seen by using the same reporter gene driven by three different promoter/enhancer sequencer or by using different reporter genes driven by the same promoter/enhancer. Cells resistant to actinomycin D, bleomycin, and nitrogen mustards were not more transfectable than the sensitive parent cells. Although the mechanism of enhanced transfection in cisplatin-resistant cells is not known, data indicated that enhanced transcription, multidrug-resistant phenotype, and methallothionein overexpression do not play a role.

Chloramphenicol O-Acetyltransferase↗