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PubMed1995

Clinical characterization of primary acquired melanosis.

PURPOSE: Primary acquired melanosis (PAM) is the name applied to flat, speckled, brown lesions of the conjunctival epithelium. Because there have been reports that many of these lesions progress to melanoma, biopsy of all PAM lesions, regardless of size, is recommended. This study was undertaken to determine the prevalence of PAM, provide a clinical description of the condition, and determine which factors are associated with its presence. METHODS: One hundred forty-six consecutive patients, who were outpatients at a corneal and external diseases service, who had no known non-European ancestry, and who were older than 10 years of age underwent careful slit lamp examination. RESULTS: The prevalence of PAM in the study population was 36%. Contrary to earlier reports, PAM is prevalent in young adults as well as in older patients. The presence of PAM was associated with southern European ancestry (P = 0.01), dark brown hair (P = 0.01), facial nevi (P = 0.03), pingueculae or pterygia (P = 0.01), hypertension (P = 0.02), cigarette smoking (P = 0.02), and the absence of ocular surface disease (P = 0.02). CONCLUSIONS: Because PAM is common, its transformation to conjunctival melanoma must be extremely rare, and biopsy of all PAM lesions is unwarranted. In the absence of known clinical risk factors for progression to melanoma, interim recommendations are made to perform biopsy only of those lesions that are widespread, large, thickened, dark, palpebral, unusually vascular, or progressive.

Adolescent↗

PubMed1995

Importance of TNF production for the curative effectiveness of low dose melphalan therapy for mice bearing a large MOPC-315 tumor.

We have previously shown the importance of the acquisition of CD8+ T cell-dependent tumor-eradicating immunity for the curative effectiveness of low dose melphalan (L-PAM, L-phenylalanine mustard) for mice bearing a large MOPC-315 tumor. Here we show the importance of TNF production for the curative effectiveness of low dose L-PAM for such tumor-bearing mice. Studies regarding the mechanism(s) through which TNF exerts its antitumor effects in L-PAM-treated MOPC-315 tumor-bearing mice (L-PAM TuB mice) revealed that MOPC-315 tumor cells are not sensitive to the cytotoxic effects of TNF either before or after the chemotherapy. However, TNF is essential for the in vitro generation of potent CTL activity by CD8+ T cells from L-PAM TuB mice. Moreover, addition of exogenous TNF to in vitro stimulation cultures of spleen cells from untreated mice bearing a large MOPC-315 tumor resulted in the generation of a greatly enhanced CTL activity against MOPC-315-associated Ags. Finally, we have previously shown that TCR V beta 8+/CD8+ T cells are involved in the curative effectiveness of low dose L-PAM for mice bearing a large MOPC-315 tumor. Here we show that TNF is important for the ability of MOPC-315-specific V beta 8+/CD8+ T cell lines from L-PAM TuB mice to bring about tumor eradication upon adoptive transfer into tumor-bearing mice. Taken together, these studies illustrate that low dose L-PAM mediates its therapeutic effectiveness for mice bearing a large MOPC-315 tumor, at least in part, via TNF production (e.g., by V beta 8+/CD8+ T cells), which in turn promotes the generation of anti-MOPC-315 CTL activity.

Animals↗

PubMed1998

Effect of porcine reproductive and respiratory syndrome virus infection on the clearance of Haemophilus parasuis by porcine alveolar macrophages.

Porcine reproductive and respiratory syndrome virus (PRRSV) infection in young piglets is frequently associated with secondary infection due to various pathogens, especially those of the respiratory tract. One of the most important mechanisms in respiratory diseases is related to the alteration of function of porcine alveolar macrophages (PAMs). The objective of this study was to determine how PRRS virus infection affects the capabilities of PAMs in the phagocytosis and destruction of Haemophilus parasuis. Phagocytosis percentages were determined in vitro and ex vivo, after collected PAMs were directly exposed to the virus of if PAMs were collected from piglets previously infected with PRRSV. In vitro experiments demonstrated that H. parasuis uptake by PAMs is only increased in the early stages of PRRSV infection (2 h post-infection). In contrast, in the ex vivo experiments it was shown that PAMs from PRRSV-infected piglets do not seem to change in their phagocytic rate until the later stages of infection. Together with a decrease in the phagocytic rate, a marked decrease in the functional ability of PAMs to kill bacteria was observed 7 d post-infection. It is hypothesized that when animals are exposed to PRRSV, there is a marked decrease in the functional ability of PAMs to kill bacteria through the release of superoxide anion, indicating a possible negative effect of the virus, at least at the macrophage level.

Animals↗

PubMed1996

Expression and processing of peptidylglycine alpha-amidating monooxygenase messenger RNA in rat prostate.

The prostate gland contains neuroendocrine cells and amidated neuroendocrine peptides whose presence has been related to aggressive forms of prostate cancer. The enzyme peptidylglycine alpha-amidating monooxygenase (PAM) is critical to the bio-synthesis of amidated peptides and is commonly present in neuroendocrine cells. By northern blot hybridization analysis, PAM mRNA was detected in similar quantities in dorsolateral and ventral prostates of 3-month-old and 13-month-old rats. Multiple forms of PAM mRNA were present whose size distribution was more similar to PAM mRNAs found in pituitary than atrium. Alternative splice sites in PAM mRNA were investigated by reverse-transcriptase polymerase chain reaction. Similar alternatively spliced forms of PAM mRNA were found in both prostate lobes, pituitary, and atrium. However, the distribution of forms in the prostate most resembled that of pituitary. Multiple forms of PAM mRNA are present in prostate and may serve as markers of neuroendocrine differentiation.

Alternative Splicing↗

PubMed2003

Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, vincristine, and prednisone compared with single-agent L-phenylalanine mustard for patients with operable breast carcinoma and positive axillary lymph nodes: 20-year results of a Southwest Oncology Group study.

BACKGROUND: Adjuvant combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil plus vincristine and prednisone (CMFVP) was compared with single-agent L-phenylalanine mustard (L-PAM) for the treatment of patients with axillary lymph node positive primary breast carcinoma over 20-years of follow-up. METHODS: Four hundred forty-one women with axillary lymph node positive breast carcinoma were randomized to receive either combination chemotherapy with cyclophosphamide (60 mg/m(2) orally every day for 1 year), fluorouracil (300 mg/m(2) intravenously [IV] weekly for 1 year), methotrexate (15 mg/m(2) IV weekly for 1 year), vincristine (0.625 mg/m(2) IV for 10 weeks), prednisone (30 mg/m(2) orally on Days 1-14, 20 mg/m(2) on Days 15-28, and 10 mg/m(2) on Days 29-42), or single-agent chemotherapy with L-PAM (5 mg/m(2) orally every day for 5 days every 6 weeks for 2 years) after undergoing surgery. Patients were stratified according to menopausal status and number of positive lymph nodes (1-3 positive lymph nodes or > 3 positive lymph nodes). Seventy-seven patients were ineligible. RESULTS: The maximum follow-up is 24 years, with a median follow-up of 21.5 years. Disease free survival and overall survival were superior with CMFVP (two-sided log-rank test; P = 0.0008 and P = 0.007, respectively). For all patients, the estimated 20-year survival rate of patients who received CMFVP was 40% compared with 27% for patients who received L-PAM. There was a substantial survival benefit for CMFVP compared with L-PAM in the subsets of premenopausal patients and patients with four or more positive lymph nodes. The estimated 20-year survival rate for premenopausal women who received CMFVP was 49% compared with 33% for premenopausal women who received L-PAM. Among women with > or = 4 positive lymph nodes, the estimated survival rate for patients who received CMFVP was 31% compared with 15% for patients who received L-PAM. Both regimens were tolerated well. Toxicity was more severe and frequent among patients who received CMFVP. CONCLUSIONS: The authors conclude that, after 20 years of follow-up, adjuvant chemotherapy with CMFVP remains superior to L-PAM for the treatment of patients with lymph node positive breast carcinoma.

Adult↗

PubMed2004

Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion.

BACKGROUND: Treatment with zoledronic acid (Zol) was compared with a dose of 90 mg of pamidronate (Pam) in breast carcinoma (BC) patients with at least 1 osteolytic lesion based on data from a Phase III, randomized trial. METHODS: Overall, 1130 patients with breast carcinoma who had all types of bone metastases (osteolytic, mixed, or osteoblastic by radiology) were randomized to receive treatment with either 4 mg of Zol or 8 mg of Zol as a 15-minute infusion or 90 mg of Pam as a 2-hour infusion every 3-4 weeks for 12 months. A skeletal-related event (SRE) was defined as a pathologic fracture, spinal cord compression, radiotherapy, or surgery to bone. RESULTS: Among all patients with BC, the proportion of those who had an SRE (primary endpoint) was comparable between treatment groups (43% of patients who received 4 mg of Zol vs. 45% of patients who received Pam). Among patients who had breast carcinoma with at least 1 osteolytic lesion (n = 528 patients), the proportion with an SRE was lower in the 4-mg Zol group compared with the Pam group (48% vs. 58%), but this did not reach statistical significance (P = 0.058). The time to first SRE was significantly longer in the 4-mg Zol group compared with the Pam group (median, 310 vs. 174 days; P = 0.013). Moreover, multiple-event analysis demonstrated significant further reductions in the risk of developing SREs over the reduction achieved with Pam (30% in the osteolytic subset [P = 0.010] and 20% for all patients with BC [P = 0.037]). CONCLUSIONS: The current data indicate that treatment with 4 mg of Zol was more effective than 90 mg of Pam in reducing skeletal complications in a subset of patients with breast carcinoma who had at least 1 osteolytic lesion at study entry.

Antineoplastic Agents↗

PubMed1986

Size and filterability of human and hamster pulmonary macrophages exposed to cigarette smoke.

Pulmonary alveolar macrophages (PAM) obtained from healthy human cigarette smokers generated greater pressure in filtration through small cylindrical pores than PAM from nonsmoking controls. A well standardized hamster smoking model was employed to study the structural basis for the impaired PAM filtration accompanying cigarette smoke exposure. Hamsters also demonstrated increased PAM filtration pressure through cylindrical pores less than half a cell diameter in size after inhalation of cigarette smoke, but not after exposure to vapor phase smoke that had been strained through a particle filter. Cigarette smoker PAM were equally filterable as control through larger diameter channels, and showed comparable improvements in filterability with cytochalasin B treatment. Altered PAM filtration was associated with the formation of characteristic cytoplasmic smoker inclusions, an increase in cell size, and loss of redundant, ruffled surface membrane. The study of smoker and control PAM separated into different sizes on the basis of variations in cell density suggested that discrepancies in cell size were insufficient to explain the filtration disparity. A loss of availability of surface membrane for deformation appeared to be the most important factor responsible for the impaired filtration.

Animals↗

PubMed1995

Effect of arsenic exposure on alveolar macrophage function. II. Effect of slightly soluble forms of As(III) and As(V).

The pulmonary toxicity of a substance depends on a number of chemical and physical characteristics, including the solubility of the compounds. In the lung, insoluble forms of metals may be more tumorigenic than soluble forms despite the fact that this effect has not been quantitated and the mechanism of action has not been elucidated. The toxic effects of slightly soluble forms of As(III) and As(V) were evaluated by determining alteration in function of pulmonary alveolar macrophages (PAM) following in vivo and in vitro exposure. Male Sprague-Dawley rats were used throughout. Twenty-four hours following intratracheal instillation of 1 mg/kg (as arsenic) of either arsenic trisulfide (As(III)) or calcium arsenate (As(V)), PAM were lavaged and analyzed for alterations in superoxide (O2-), and tumor necrosis factor (TNF-alpha) production. There were no differences in bronchoalveolar lavage fluid TNF-alpha. PAM lavaged from As(V)-exposed animals showed significant increases in O2- production and in basal release of TNF-alpha. PAM lavaged from animals receiving As(III) did not show significant alterations. To test the direct effects of arsenic, PAM were lavaged from control animals and exposed to concentrations of 0.1 to 300 micrograms/ml arsenic in vitro for up to 24 hr. Doses used were not cytotoxic to PAM, since LDH release was not significantly increased. Significant dose-dependent inhibition of O2- production was only evident after 24 hr exposure to arsenicals. Both As(III) and As(V) produced inhibition at concentrations of 10 micrograms/ml. Suppression of LPS-induced release of TNF-alpha also occurred at similar concentrations for both arsenicals (4-5 micrograms/ml). Neither arsenical inhibited prostaglandin E2 production. Measurement of soluble arsenic concentrations indicated dissolution of the compounds could not account for all of the effects seen. Arsenic-induced alteration in PAM function may compromise host defense.

Animals↗

PubMed1986

The difference between 5-fluorouracil and melphalan in their ability to promote antitumor immune response against MOPC-315 plasmacytoma.

The anticancer chemotherapeutic drugs melphalan (L-phenylalanine mustard; L-PAM), 5-fluorouracil (5-FU), methotrexate (MTX), and daunorubicin (DAU) were tested for their toxic activity against MOPC-315 tumor cells in vitro. L-PAM, 5-FU, and DAU had a marked toxic effect whereas MTX did not affect the rate of thymidine incorporation in the tumor cells. L-PAM (7.5 mg/kg) induced permanent regression of large s.c. MOPC-315 plasmacytoma tumors, 5-FU (200-250 mg/kg) induced transient regression of MOPC-315 tumors with reappearance starting on the 6th day after the 5-FU injection and DAU (5 mg/kg) was not effective. L-PAM treatment restored the cytotoxic potential of spleen cells of tumor-bearing mice against target MOPC-315 tumor cells whereas spleen cells from tumor-bearing mice treated with 5-FU were unable to mount a cytotoxic response. L-PAM and 5-FU were also assayed for their effect in vitro on induction of suppressor T cells by ConA. L-PAM treatment in vitro markedly reduced the induction of suppressor T cells by ConA whereas 5-FU had no effect. It is suggested that anticancer chemotherapeutic drugs can be classified in "immunopromoting" (L-PAM as prototype) and "nonimmunopromoting" (5-FU as prototype) on the basis of their effect in vivo on established tumors and their effect on induction of suppressor T cells by ConA.

Adjuvants, Immunologic↗

PubMed1987

Petroleum hydrocarbon toxicity in vitro: effect of n-alkanes, benzene and toluene on pulmonary alveolar macrophages and lysosomal enzymes of the lung.

The in vitro effects of straight chain alkanes (nC6-nC10), benzene and toluene on pulmonary alveolar macrophages (PAM) of rats and rabbits was studied. The concentrations used ranged from 0.02 to 1.0 mM. All hydrocarbons used in the study were cytotoxic to isolated cultured PAM cells in a dose-dependent manner. The LC50 for these hydrocarbons towards rat PAM cells was estimated to be 1.0 mM for nC8, 2 mM for nC7, 5 mM for nC9 and 10 mM for nC6, nC10, benzene and toluene. Rabbit PAM cells were more sensitive to the hydrocarbons, resulting in and LC50 half that for rat PAM cells. Hydrocarbons also caused extracellular release of the lysosomal enzymes cathepsin D (EC 3.4.23.5) and cathepsin B (EC 3.4.22.1) in a manner corresponding with cell damage. There was more cathepsin D activity released from cells than cathepsin B. In addition, hydrocarbons also caused the release of cathepsin B and D from isolated lysosomes, and there was 10-15% more enzyme activity released in the culture medium of lysosomes exposed to concentrations of 0.5 and 1.0 mM compared to PAM cell cultures of either rats or rabbits. Hydrocarbons also caused loss of cell respiration and stimulated a dose-dependent and a time-dependent increase in lipid peroxidation. The two alkanes nC7 and nC8 caused the greatest increase in lipid peroxidation and the greatest loss of cell respiration. The results indicate that there is a relationship between chain length of alkanes and their cytotoxicity to PAM cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkanes↗

PubMed1989

The relative contribution of resident pulmonary alveolar macrophage and inflammatory polymorphonuclear neutrophils in host resistance to pulmonary infection by Candida albicans.

Cortisone (CA) or cyclophosphamide (Cy) treatment of mice was used to investigate the relative contributions of pulmonary alveolar macrophages (PAM) and inflammatory neutrophils (PMN) in the initial defense against intratracheal challenge (IT) with Candida albicans. Mice treated with either CA or Cy were susceptible to IT challenge with 10-100 x less C. albicans than were untreated mice. Untreated mice rapidly eliminated C. albicans from their lungs with the majority of the organisms being cleared within three hours of challenge. Mice treated with CA initially cleared some of the C. albicans but were unable to clear all the C. albicans as did the untreated mice. Mice treated with Cy were unable to clear C. albicans from their lungs. Candida albicans did not disseminate from the lungs of untreated mice, while in both of the treated groups, C. albicans disseminated to the liver, spleen, brain and kidneys, rapidly killing the treated hosts. Analysis of the changes in cells in lung lavage fluids collected at various times after C. albicans challenge, revealed that large numbers of PMN accumulated in the lungs of both untreated and CA-treated mice, whereas PMN were virtually undetectable in lavage fluids from Cy-treated mice. Resident PAM from untreated mice were able to kill approximately 70% of 10(5) C. albicans in a 3 hr in vitro killing assay. By contrast, at similar effector:target ratios, resident PAM from Cy-treated mice killed only about 20% of the inoculum and resident PAM from CA-treated mice were unable to kill C. albicans. PMNs from both untreated and CA-treated mice killed approximately 70% of 10(5) C. albicans in vitro. The data indicates that both PAM and PMN were critical to the initial clearance of C. albicans from pulmonary tissue. The accumulation of PMN in the lungs appeared to be required for the complete clearance of C. albicans from the lungs yet was not sufficient to inhibit dissemination of C. albicans from the lungs in CA-treated mice. The presence of PAM with in vitro candidacidal abilities appeared to be required for both the clearance of C. albicans and inhibition of dissemination of C. albicans from the lungs. Compromise of either PAM or PMN function can lead to increased pulmonary susceptibility to C. albicans.

Animals↗

PubMed1979

Aryl hydrocarbon hydroxylase activity in pulmonary alveolar macrophages and lymphocytes from lung cancer and noncancer patients: a correlation with family histories of cancer.

Aryl hydrocarbon hydroxylase (AHH) activity was measured in pulmonary alveolar macrophages (PAMs) and peripheral blood lymphocytes from cigarette smokers with and without primary lung cancer. Frequency distribution analysis of AHH induction ratios for the two groups revealed an increased number of individuals in the lung cancer patient group with high lymphocyte induction values (P less than 0.05). A similar increase was not shown for high-PAM AHH values in lung cancer patients (P greater than 0.2). When individual PAM and lymphocyte AHH values were compared between noncancer and lung cancer patients, a positive correlation was observed for noncancer patients (r=0.195, P less than 0.001), but no correlation of these values was noted for lung cancer patients. The lung cancer patients were divided into three subgroups of patients showing (I) high PAM and low lymphocyte AHH levels, (II) low PAM and low lymphocyte AHH levels, and (III) low PAM and high lymphocyte AHH levels. When the incidence of family history of cancer was compared for these subgroups, no family cancer history was recorded for persons in subgroup II; however, individuals in subgroups I and III presented family cancer history incidence of 9.5% and 39.3%, respectively. Patients in group III averaged 6 years younger than those in group I. These data suggest that familial factors may be identified among lung cancer patients and that these factors appear to associate as either a cause of an effect with the capacity of pulmonary alveolar macrophages and lymphocytes to be induced for AHH. The data support the hypothesis that high AHH values may be characteristic of lung cancer patients but show that enzyme values determined from a single tissue, either PAMs or lymphocytes, may not be appropriate for showing whether high AHH inducibility is correlated with lung cancer.

Aryl Hydrocarbon Hydroxylases↗

PubMed1983

Adjuvant chemotherapy in stage-II breast cancer: an overview of the NSABP clinical trials.

Data derived from 1848 patients entered into three adjuvant chemotherapy protocols are presented. The three studies were performed sequentially and were designed to identify patient subsets responding to one, two, or three chemotherapeutic agents. Comparison of disease-free survival in patients receiving L-PAM or placebo disclosed that L-PAM was beneficial in patients less than or equal to 49 years of age, but not in women greater than or equal to 50 years. Further analysis indicated that the subset of patients less than or equal to 49 years with 1-3 positive nodes sustained the greatest increment in disease-free survival with single-agent L-PAM. The addition of 5-FU to L-PAM was superior to L-PAM alone in patients greater than or equal to 50 years of age, particularly those with greater than or equal to 4 positive nodes. The three-drug combination of L-PAM, 5-FU, and methotrexate failed to provide a benefit over and above that achieved by the L-PAM-5-FU combination in all subsets examined. The results underscore the heterogeneous response to chemotherapy demonstrated by patient subsets characterized on the basis of age and nodal status. The implications of the findings relative to the current status of adjuvant therapy are discussed.

Adult↗

PubMed2003

Positive assortative mating with selection restrictions on group coancestry enhances gain while conserving genetic diversity in long-term forest tree breeding.

Selection and mating principles in a closed breeding population (BP) were studied by computer simulation. The BP was advanced, either by random assortment of mates (RAM), or by positive assortative mating (PAM). Selection was done with high precision using clonal testing. Selection considered both genetic gain and gene diversity by "group-merit selection", i.e. selection for breeding value weighted by group coancestry of the selected individuals. A range of weights on group coancestry was applied during selection to vary parent contributions and thereby adjust the balance between gain and diversity. This resulted in a series of scenarios with low to high effective population sizes measured by status effective number. Production populations (PP) were selected only for gain, as a subset of the BP. PAM improved gain in the PP substantially, by increasing the additive variance (i.e. the gain potential) of the BP. This effect was more pronounced under restricted selection when parent contributions to the next generation were more balanced with within-family selection as the extreme, i.e. when a higher status effective number was maintained in the BP. In that case, the additional gain over the BP mean for the clone PP and seed PPs was 32 and 84% higher, respectively, for PAM than for RAM in generation 5. PAM did not reduce gene diversity of the BP but increased inbreeding, and in that way caused a departure from Hardy-Weinberg equilibrium. The effect of inbreeding was eliminated by recombination during the production of seed orchard progeny. Also, for a given level of inbreeding in the seed orchard progeny or in a mixture of genotypes selected for clonal deployment, gain was higher for PAM than for RAM. After including inbreeding depression in the simulation, inbreeding was counteracted by selection, and the enhancement of PAM on production population gain was slightly reduced. In the presence of inbreeding depression the greatest PP gain was achieved at still higher levels of status effective number, i.e. when more gene diversity was conserved in the BP. Thus, the combination of precise selection and PAM resulted in close to maximal short-term PP gain, while conserving maximal gene diversity in the BP.

Computer Simulation↗

PubMed1983

Malathion and phenthoate carboxylesterase activities in pulmonary alveolar macrophages as indicators of lung injury.

Malathion and phenthoate carboxylesterase activities were investigated in pulmonary alveolar macrophages (PAM) in Sprague-Dawley rats. PAM was found to be capable of hydrolyzing phenthoate at a faster rate than malathion. Oral administration to rats with O,O,S-trimethyl phosphorothioate (OOS-Me), a pneumotoxic impurity present in technical grades of malathion and phenthoate, increased the activities of these esterases in PAM without affecting an activity in lung microsomal carboxylesterase. The time course study indicated that this increase was maximal on Day 1 following treatment with OOS-Me at 20 and 40 mg/kg of doses. To assess the usefulness of measuring these esterases in PAM as an indicator of lung damage, paraquat and bromobenzene were administered to rats with treatment regimens which have been shown previously to result in histopathologically demonstrable pneumotoxicity. Malathion and phenthoate carboxylesterase activities in PAM were increased by two- to threefold following treatment with paraquat or bromobenzene. These treatments also increased lung microsomal malathion carboxylesterase activity by threefold. Furthermore, infection of rats with Pseudomonas aeruginosa by intratracheal inoculation increased malathion and phenthoate carboxylesterase activities in PAM by two- to threefold without increasing these activities in lung microsomes. These results indicate that PAM may play a significant role in detoxifying airborne malathion and phenthoate when inhaled. Furthermore, the activities of malathion and phenthoate carboxylesterases may be useful for detecting lung injury produced by pneumotoxic chemicals as well as bacterial infection.

Animals↗

PubMed1986

The effects of purine nucleoside analogs on the response of the RIF-1 tumor to melphalan in vivo.

The effect of several purine nucleoside analogs on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumor in vivo was investigated. All the analogs tested--3'-deoxyguanosine (3'-dG), 3'-deoxyadenosine (3'-dA), and N6-butyryl-3'-deoxyadenosine (N6-BC)--at a dose of 100 mg/kg, enhanced the tumor cell killing by L-PAM as measured by an in vivo/in vitro procedure. This enhancement was maximal when the drugs were given simultaneously. The mean enhancement ratios (ER's) determined from the L-PAM dose response curves were 1.4 for 3'-dG, 1.3 for 3'-dA, and 1.4 for N6-BC. A similar modification of the L-PAM-induced depression of white blood cell counts was not obtained. A large single dose of L-PAM (8 mg/kg) produced a transient drop in mouse body temperature. The analog 3'-dG (100 mg/kg) increased and prolonged this hypothermic effect. In addition 3'-dG also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 28 minutes to 35 minutes. The enhancement of the efficacy of L-PAM by these analogs probably results from this pharmacokinetic effect.

Animals↗

PubMed2005

Behavioral, endocrine and immunological characteristics of a murine model of premature aging.

We have previously shown that differences in life span among members of Swiss mouse populations appear to be related to their exploration of a T-maze, with a slow exploration ('slow mice') being linked to alteration of spontaneous behavior and monoaminergic systems, impaired immune function and shorter life span. In general these traits resemble some of the characteristics of chronologically old animals. Thus, we proposed the 'slow mice' as a model of prematurely aging mice (PAM). Now, we have compared female PAM with non-prematurely aging mice (NPAM) as regards a number of behavioral, endocrine and immunological parameters which were studied under both basal and stress conditions. In the present study the animals were chronologically younger than those used in our previous work. When compared to NPAM, the PAM showed increased anxiogenic-like responses in the plus-maze, increased basal corticosterone levels and decreased corticosterone responses to stress. The PAM also showed a decreased natural killer activity as well as decreased lymphoproliferative responses to mitogens. Moreover, the mitogen-induced lymphoproliferative responses of the PAM appeared to be more susceptible to stress. The data indicate that certain characteristics of the PAM are already present in animals of very young chronological age and provide new information for a more complete characterization of the PAM from a neuroimmunoendocrine viewpoint.

Age Factors↗

PubMed2006

Dexamethasone conjugated poly(amidoamine) dendrimer as a gene carrier for efficient nuclear translocation.

Nuclear membrane is one of the main barriers in polymer-mediated intracellular gene delivery. It was previously reported that glucocorticoid receptor dilated the nuclear pore and translocated into nucleus when it bound to its ligand, glucocorticoid. This suggests that the transport of DNA into nucleus may be facilitated by glucocorticoid. In this study, a glucocorticoid, dexamethasone, was conjugated to polyamidoamine (PAMAM) dendrimer and the effect of the conjugation was investigated. The PAMAM-Dexamethasone (PAM-Dexa) was synthesized by the one-step reaction using Traut's reagent. PAM-Dexa/plasmid DNA complex was completely retarded at a 1/1 weight ratio (polymer/DNA) in a gel retardation assay. PAM-Dexa protected DNA from DNase I for more than 60 min. PAM-Dexa/plasmid DNA complex showed the highest transfection efficiency to 293 cells at a 0.8/1 weight ratio. At this ratio, PAM-Dexa had higher transfection efficiency than PAMAM. Especially in the presence of serum during the transfection, the transfection efficiency of PAM-Dexa was higher than that of PAMAM or PEI by one order of magnitude. In addition, more PAM-Dexa/DNA complexes were observed in the nucleus region than PAMAM/DNA from the confocal microscopy studies. These results indicated that the technique with dexamethasone might be useful for the gene delivery using polymeric gene carriers and the development of efficient polymer vectors.

Active Transport, Cell Nucleus↗