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D Conlon

Publications and source records attributed to D Conlon.

12 recordsLinked to original sources
PubMed1997

Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]isoquinoline-1,3-diones.

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.

1-Naphthylamine↗
PubMed1996

Bis-naphthalimides 3: synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl] alkanediamines.

The bis-naphthalimides are a new class of antitumor agent. Previously, we have described initial synthetic series which established that two naphthalimide chromophores joined by polyamine linkers can produce agents with antitumor activity. We now extend these studies to describe the synthesis of a N,N'-bis[1,8-naphthalimido)-ethyl]alkanediamine series and examine the alkyl linker and chromophore substitution requirements for optimal antitumor activity. As a result, a bis-naphthal-imidoethyl derivative with no chromophore substitution and a NH-(CH2)3-NH bridge was identified. This agent (LU 79553) had both potent cellular cytotoxicity (IC50 = 0.014 microM) and was curative against MX-1 tumors grown in athymic mice. It has now been selected for clinical development.

Amines↗
PubMed1995

Effect of ageing and propranolol administration on myocardial beta-adrenoceptor receptor function in mature rats.

Ageing is accompanied by diminishing myocardial tissue beta-adrenoceptor responses. The relative contribution of maturation and senescence to reported age-related changes in cell-surface beta-adrenoceptor dysfunction has not been established, since previous investigation has incorporated young rats lacking full maturity. We have examined myocardial ventricle membrane beta-adrenoceptor function in mature young (6 month) and old (26 month) male Wistar rats and the effect of propranolol infusion for seven days on beta-adrenoceptor function in these groups. beta 1-adrenoceptors comprised 63-72% of total beta-adrenoceptor density in both groups. beta 1-adrenoceptor densities were similar in young and old rats (young, 20.4 +/- 2.3; old, 24.7 +/- 1.4 fmol/mg protein +/- S.E.). beta 2-adrenoceptor densities were higher in older rats (young, 8.2 +/- 0.5, n = 9; old, 13.6 +/- 1.8, n = 9 fmol/mg protein +/- S.E., P < 0.025). Subcutaneous infusion of propranolol for seven days with miniosmotic pumps was accompanied by an increase in beta 1- and beta 2-adrenoceptor densities in young rats only (beta 1-, 38%, P < 0.05; beta 2- 52%, P < 0.025). beta 1-adrenoceptor agonist affinity and adenylate cyclase response to isoprenaline, GTP, Gpp(NH)p, Mn2+ and forskolin were not affected by age or propranolol infusion in either age-group. These findings demonstrate that male Wistar rats do not exhibit changes in myocardial ventricle beta-adrenoceptor-G-protein coupling capacity or adenylate cyclade activation with ageing beyond maturity.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

Amides↗
PubMed1994

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix GLA protein in vitro.

The role of the vitamin K dependent proteins, osteocalcin which is bone specific and matrix Gla protein (MGP) found in many tissues, has been studied by inhibition of synthesis of their characteristic amino acid, gamma-carboxyglutamic acid (Gla) with the anticoagulant sodium warfarin. The effect of sodium warfarin on expression of these proteins, and other phenotypic markers of bone and cartilage during cellular differentiation and development of tissue extracellular matrix, was examined in several model systems. Parameters assayed include cell growth (reflected by histone gene expression) and collagen types I and II, osteopontin, alkaline phosphatase, and mineralization. Studies were carried out in calvarial bone organ cultures, normal diploid rat osteoblast and chondrocyte cultures, and rat osteosarcoma cell lines ROS 17/2.8 and 25/1. In normal diploid cells, warfarin consistently stimulated cell proliferation (twofold). In osteoblast cultures, MGP mRNA levels were generally increased (three to tenfold). Notably, MGP mRNA levels were not affected in chondrocyte cultures, either with chronic or acute warfarin treatments. Osteocalcin mRNA levels and synthesis were decreased up to 50% in ROS 17/2.8 cells and in chronically treated (1 and 5 micrograms/ml sodium warfarin) rat osteoblast cultures after 22 days. Early stages of osteoblast phenotype development from the proliferation period to initial tissue formation (nodules) appeared unaffected; while after day 14, further growth and mineralization of the nodule areas were significantly decreased in warfarin-treated cultures. In summary, warfarin has opposing effects on the expression of two vitamin K dependent proteins, MGP and osteocalcin, in osteoblast cultures and MGP is regulated differently between cartilage and bone as reflected by cellular mRNA levels. Additionally, warfarin effects expression of nonvitamin K dependent proteins which may reflect the influence of warfarin on endoplasmic reticulum associated enzymes.

Animals↗
PubMed1992

Glucocorticoids promote development of the osteoblast phenotype by selectively modulating expression of cell growth and differentiation associated genes.

To understand the mechanisms by which glucocorticoids promote differentiation of fetal rat calvaria derived osteoblasts to produce bone-like mineralized nodules in vitro, a panel of osteoblast growth and differentiation related genes that characterize development of the osteoblast phenotype has been quantitated in glucocorticoid-treated cultures. We compared the mRNA levels of osteoblast expressed genes in control cultures of subcultivated cells where nodule formation is diminished, to cells continuously (35 days) exposed to 10(-7) M dexamethasone, a synthetic glucocorticoid, which promotes nodule formation to levels usually the extent observed in primary cultures. Tritiated thymidine labelling revealed a selective inhibition of internodule cell proliferation and promotion of proliferation and differentiation of cells forming bone nodules. Fibronectin, osteopontin, and c-fos expression were increased in the nodule forming period. Alkaline phosphatase and type I collagen expression were initially inhibited in proliferating cells, then increased after nodule formation to support further growth and mineralization of the nodule. Expression of osteocalcin was 1,000-fold elevated in glucocorticoid-differentiated cultures in relation to nodule formation. Collagenase gene expression was also greater than controls (fivefold) with the highest levels observed in mature cultures (day 35). At this time, a rise in collagen and TGF beta was also observed suggesting turnover of the matrix. Short term (48 h) effects of glucocorticoid on histone H4 (reflecting cell proliferation), alkaline phosphatase, osteopontin, and osteocalcin mRNA levels reveal both up or down regulation as a function of the developmental stage of the osteoblast phenotype. A comparison of transcriptional levels of these genes by nuclear run-on assays to mRNA levels indicates that glucocorticoids exert both transcriptional and post-transcriptional effects. Further, the presence of glucocorticoids enhances the vitamin D3 effect on gene expression. Those genes which are upregulated by 1,25(OH)2D3 are transcribed at an increased rate by dexamethasone, while those genes which are inhibited by vitamin D3 remain inhibited in the presence of dexamethasone and D3. We propose that the glucocorticoids promote changes in gene expression involved in cell-cell and cell-extracellular matrix signaling mechanisms that support the growth and differentiation of cells capable of osteoblast phenotype development and bone tissue-like organization, while inhibiting the growth of cells that cannot progress to the mature osteoblast phenotype in fetal rat calvarial cultures.

Alkaline Phosphatase↗
PubMed1992

The effect of donor age on human fibroblast beta-adrenergic receptor response and agonist-induced desensitization.

Aging has been associated with changes in beta-adrenergic receptor (beta-receptor) function in several tissues. The relative contribution of cellular aging and age-related changes in homeostatic regulation of receptor function is unknown. We have examined beta-receptor function in fibroblasts of young and old donors (young: mean age 31.2 +/- 0.8 years +/- S.E., n = 6; old: mean age 81.8 +/- 0.6 years +/- S.E., n = 6). Beta-receptor responses to isoproterenol (ISO), (1 microM) were similar in the two groups. The concentration of ISO required for 50% maximal beta-receptor-mediated cyclic AMP production (EC50) was similar in both groups. Fibroblast beta-receptor density was also similar in young and old groups. ISO-induced beta-receptor desensitization was both dose- and time-dependent. Submaximal desensitization by acute exposure (30 min) to ISO (1 mM) caused similar levels of beta-receptor desensitization in young (42.5 +/- 2.5%) and old (42.8 +/- 2.8%) groups and a similar increase in ISO EC50. These findings demonstrate that aging in vivo does not cause changes in fibroblast beta-receptor regulation that are retained in culture.

Adult↗
PubMed1991

Hepatic beta-adrenoceptor adaptation during propranolol administration is impaired in aging rats.

Aging has been associated with changes in beta-adrenoceptor responses and adaptation to prolonged removal of catecholamine stimulation. We have examined the effect of chronic propranolol administration on rat hepatic membrane beta-adrenoceptor density, agonist affinity and response in young (6-7 months) and old (26-7 months) male Wistar rats. Propranolol administration via miniosmotic pumps for 7 days resulted in similar and sustained plasma propranolol levels (approximately 100 ng/ml) in old and young rats. Pretreatment beta-adrenoceptor responses to isoprenaline were significantly higher in old rats. Propranolol administration was associated with significant increases in beta-adrenoceptor response and density (Bmax) in young rats only. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) responses to prostaglandin E1 (PGE1), guanosine triphosphate (GTP), 5'-guanyl-imidodiphosphate (Gpp(NH)p), forskolin and Mn2+ were not significantly different between young and old rats and were not affected by propranolol administration. Neither aging or propranolol administration was associated with a change in beta-adrenoceptor agonist affinity. These findings demonstrate elevated hepatic beta-adrenoceptor response and impaired hepatic beta-adrenoceptor adaptation to beta-adrenoceptor blockade in aging rats.

Adaptation, Physiological↗
PubMed1991

The use of visual information by house flies, Musca domestica (Diptera: muscidae), foraging in resource patches.

House flies, Musca domestica, respond to visual contrasts on the substrate if a resource is associated with the contrasting patterns. Visible resource patch boundaries serve as a signal to flies that they are about to leave a rewarding patch. Searching flies respond to such visual information by walking along the resource patch boundary and turning back into the patch at its edge. This edge detection and response serve as a mechanism for flies with visual cues to stay in a rewarding patch and locate more resources within it. The intensity of their response correlates with the quality of the resource. In the absence of visual cues, patch shape affects foraging success; flies find more resources in circular than in linear resource distributions. The effects of visual cues, however, render patch shape unimportant. Various substrate contrasts are effective as resource information for flies: dark (e.g., green) figures on bright (e.g., white) backgrounds or bright figures on dark backgrounds. Responses to substrate contrasts measured in this study indicate that, over the short term, house flies can learn a visual cue associated with a food source.

Animals↗
PubMed1975

Two-step electrocardiogram for chest pain reported on multiphasic screening.

Among 264 consecutive persons (142 men, 122 women) greater than or equal to 35 years of age presenting for multiphasic screening examination, 85 (54 men, 31 women) reported chest pain. In most, the pain was not typical of coronary artery disease. The two-step exercise electrocardiogram (ECG) was positive (greater than or equal to 0.5-mm ischemic ST depression) in 21% of the patients who reported pain and in 19.5% of 66 randomly selected, similarly examined controls without chest pain (36 men, 30 women) (difference not significant). Females with positive ECGs (5-mm or 1-mm depression) predominated over males greater than or equal to 5:1 in the chest pain group and greater than 3:1 in controls. This study indicates that the routine two-step exercise ECG is not helpful in detecting ischemic heart disease in persons reporting chest pain during their multiphasic screening examination.

Adult↗