In vitro fertilization-embryo transfer in nonhuman primates: the technique and its applications.
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Animal Welfare↗
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Androgen depletion activates telomerase in the prostate of the nonhuman primate, Macaca mulatta.
BACKGROUND: The activity of telomerase, an enzyme that synthesizes telomeric repeats at the ends of chromosomes, is not detectable in normal human prostate. However, the majority of human prostate cancers exhibit telomerase activity. Since androgens play a major role in prostate tumorigenesis, we investigated the effect of androgen-depletion on the expression of telomerase activity in the prostate. METHODS: Adult male rhesus monkeys were either bilaterally castrated or subjected to sham surgery (n = 5 each). Approximately 6 weeks later, the animals were killed and the different regions of the prostate gland were removed and frozen immediately. Telomerase activity was assayed using the telomeric repeat amplification protocol. RESULTS: All five regions of the prostate from sham operated control animals failed to exhibit telomerase activity. In the castrated monkey, all regions of the prostate, except for the anterior lobe, expressed high levels of telomerase activity. CONCLUSIONS: Our results indicate that in monkeys, androgen-ablation leads to up-regulation of telomerase activity. The negative-regulation of telomerase activity by androgens is probably lost during prostate tumorigenesis.
Androgens↗
Experimental prostatitis in nonhuman primates: I. Bacterial adherence in the urethra.
Both man and monkey possess urothelial (transitional cell) receptors for P-fimbriae of Escherichia coli; however, the male urethra has pseudostratified columnar cells. We studied adherence using scanning electron microscopy and found that P-fimbriae were the principal mediators of adherence to these cells as well. The monkey, therefore, should be a good model for the study of the ascending route of infection in prostatitis, the route thought to occur in man.
Animals↗
The efficacy of recombinant thrombopoietin in murine and nonhuman primate models for radiation-induced myelosuppression and stem cell transplantation.
Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys for studying thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the mid-lethal dose of 5 Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow cells, and potentiated the response to growth factors such as GM-CSF and G-CSF. In contrast to the results in the 5 Gy TBI model, TPO was ineffective following transplantation of limited numbers of autologous bone marrow or highly purified stem cells in monkeys conditioned with 8 Gy TBI. In the 5 Gy model, a single dose of TPO augmented by GM-CSF 24 h after TBI was effective in preventing thrombocytopenia. The strong erythropoietic stimulation may result in iron depletion, and TPO treatment should be accompanied by monitoring of iron status. This preclinical evaluation thus identified TPO as a potential major therapeutic agent for counteracting radiation-induced pancytopenia and demonstrated pronounced stimulatory effects on the reconstitution of immature CD34+ hemopoietic cells with multilineage potential. The latter observation explains the potentiation of the hematopoietic responses to G-CSF and GM-CSF when administered concomitantly. It also predicts the effective use of TPO to accelerate reconstitution of immature hematopoietic cells as well as possible synergistic effects in vivo with various other growth factors acting on immature stem cells and their direct lineage-committed progeny. The finding that a single dose of TPO might be sufficient for a clinically significant response emphasizes its potency and is of practical relevance. The heterogeneity of the TPO response encountered in the various models used for evaluation points to multiple mechanisms operating on the TPO response and heterogeneity of its target cells. Mechanistic mouse studies made apparent that the response of multilineage cells shortly after TBI to a single administration of TPO is quantitatively more important for optimal efficacy than the lineage-restricted response obtained at later intervals after TBI and emphasized the importance of a relatively high dose of TPO to overcome initial c-mpl-mediated clearance. Further elucidation of mechanisms determining efficacy might very well result in a further improvement, e.g., following transplantation of limited numbers of stem cells. Adverse effects of TPO administration to myelosuppressed or stem cell transplanted experimental animals were not observed.
Animals↗
Measurements of in vivo megakaryocytopoiesis: studies in nonhuman primates and patients.
In vivo megakaryocytopoiesis was directly analyzed for megakaryocyte (MK) number and mass, expression of lineage-specific and myeloid differentiation markers, and cell maturation as determined by size, granularity and ploidy. Using a rapid method for multiparameter correlative analysis with three-color flow cytometry (FCM) and a single-argon-ion-laser analyzer, cell DNA in aspirated marrow was stained with 7-amino-actinomycin D, and surface membrane receptors were analyzed with antibodies and cytokines labeled with fluorescein, phycoerythrin and peridinin chlorophyll protein. MKs expressing glycoprotein (GP) IIb/IIIa were enumerated in relation to the nucleated erythroid precursors expressing glycophorin A, and MK diameters were measured by time-of-flight technique. In human marrow (n = 10) the average MK diameter is 37 microm (range: 21 microm for 2N to 56 microm for 64N cells), volume is 26 x 10(3) fL, and MK number is 10 x 10(6)/kg, giving a total MK mass of 26 x 10(10) fL/kg. The modal ploidy is 16N. In essential thrombocythemia patients (n = 10) with a mean platelet count of 907 +/- 23 x 10(6)/L, MK number and volume increased twofold with modal ploidy of 32N, and MK mass fourfold the normal value. After reducing the platelet count to 353 +/- 42 x 10(6)/L with anagrelide therapy, MK number and volume decreased with modal ploidy of 16N, resulting in reduced MK mass by 50%. By contrast, patients with chronic myelogenous leukemia (n = 3) showed an increase in small MKs with a modal ploidy of 8N. In non-human primates, treatment with interleukin 6 or GM-CSF increased MK volume and ploidy with a variable increase in cell number and platelet counts. Treatment with recombinant human MK growth and development factor (n = 6, 5 microg/kg for 28 days) increased platelet count fivefold, MK number fourfold, MK volume twofold and total mass sevenfold. Using three-color FCM, marrow MKs labeled for GPIIb/IIIa and stained for DNA expressed high levels of von Willebrand factor with a high resolution of 2N/4N MKs from the total marrow cells. The expression of myeloid markers including CD36, CD45 and IgG-Fc gammaRII CDw32 correlated directly with increasing cell maturation, concordant with the expression of GPIIb/IIIa and GPIb. Conversely, the expression of HLA-DR declined with maturation. We conclude that pathophysiologic and therapeutic changes in megakaryocytopoiesis in vivo are readily quantified using FCM measurements.
Animals↗
Transduction of hematopoietic stem cells in humans and in nonhuman primates.
Primitive hematopoietic progenitor and stem cells have been pursued as highly desirable targets for genetic therapy. Retroviral vectors have been used for the majority of preclinical and clinical studies directed at these cells; however, both preclinical and early clinical studies indicate that the gene transfer efficiency of the current generation of vectors using known transduction conditions into primate and human repopulating stem cells is too low to be of clinical utility in most situations. In this presentation I will summarize the status of our completed and ongoing clinical genetic marking trials, and describe our efforts in the laboratory and use of primate transplantation models to improve on these results.
Animals↗
The efficacy of recombinant TPO in murine And nonhuman primate models for myelosuppression and stem cell transplantation.
Radiation-induced pancytopenia proved to be a suitable model system in mice and rhesus monkeys to study thrombopoietin (TPO) target cell range and efficacy. TPO was highly effective in rhesus monkeys exposed to the midlethal dose of 5-Gy (300 kV x-rays) TBI, a model in which it alleviated thrombocytopenia, promoted red cell reconstitution, accelerated reconstitution of immature CD34+ bone marrow (BM) cells and potentiated the response to growth factors such as GM-CSF and G-CSF. The accelerated reconstitution of BM CD34+ cells appeared to be reflected by a similar rise in peripheral blood CD34+ cells, both being augmented by concomitant GM-CSF. However, TPO was ineffective following transplantation of limited numbers of autologous BM or highly purified stem cells in monkeys conditioned with 8-Gy TBI. In the 5-Gy model, a single dose of TPO 24 h after TBI was effective in preventing thrombocytopenia and was augmented by GM-CSF. The strong erythropoietic stimulation may result in iron depletion and TPO treatment should be accompanied by monitoring of iron status. In mice, similar observations were made and the importance of dose and dose schedule for stimulation of multilineage repopulating cells versus the lineage-dominant thrombopoietic response studied in detail.
Animals↗
Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates.
Salvinorin A, a potent hallucinogen isolated from the leaves of Salvia divinorum, has gained popularity among adolescents in the USA. No detailed study of the pharmacokinetics has been conducted in vivo. The present study investigates the in vivo pharmacokinetics of salvinorin A (0.032 mg/kg, i.v. bolus) in rhesus monkeys (n=4, 2 male, 2 female). The elimination t(1/2) was rapid (56.6+/-24.8 min) for all subjects. Pharmacokinetic differences (distribution t(1/2), elimination t(1/2), and AUC) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, is observed to accumulate ex vivo; however, in this study it never reached the limit of detection.
Animals↗
PET imaging of striatal dopamine D2 receptors in nonhuman primates: increases in availability produced by chronic raclopride treatment.
Previous research using positron emission tomography (PET) in monkeys has shown that attaining social dominance can result in increased DA D2 receptor availability and attenuated sensitivity to the reinforcing effects of cocaine. The present study utilized a within-subjects design to determine whether chronic treatment with the D2 receptor antagonist raclopride could similarly increase D2 receptor availability. Using the D2-selective radioligand [(18)F]fluoroclebopride (FCP), three adult male cynomolgus monkeys were scanned before and after chronic treatment with raclopride (0.01 mg/kg per h for 30 +/- 1 day) administered by a subcutaneous osmotic pump. Food-reinforced operant behavior was assessed during treatment. A transitory decrease in responding was observed during the initial eight days of raclopride treatment. Tolerance developed by the tenth session, and responding remained at baseline levels for the duration of treatment and after treatment was discontinued. Averaged across monkeys, chronic raclopride administration increased FCP distribution volume ratios (DVRs) between 12 and 20% in the caudate nucleus, putamen, and anterior cingulate cortex. When monkeys were re-scanned 9-12 months after termination of raclopride treatment, FCP DVRs remained elevated in two subjects, and decreased below baseline levels in the third monkey. Considering the reported 2% test/retest variability for FCP, these findings indicate that chronic treatment with a D2 receptor antagonist can produce large increases in D2 receptor availability as measured with PET. Individual differences in rates of recovery were observed, such that the increases in DVR persisted in two of three subjects.
Animals↗
Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride.
PET measurements of stimulant-induced dopamine (DA) release are typically performed with antagonist radioligands that bind to both the high- and low-affinity state of the receptor. In contrast, an agonist radioligand binds preferentially to the high-affinity state and is expected to have greater sensitivity to DA, which is the endogenous agonist. [(11)C]MNPA, (R)-2-CH(3)O-N-n-propylnorapomorphine (MNPA), is a D(2) agonist radioligand with subnanomolar affinity to the D(2) receptor. The aim of the present study is to assess and compare the sensitivity of the agonist radioligand [(11)C]MNPA and antagonist radioligand [(11)C]raclopride to synaptic DA levels. Four cynomolgus monkeys were examined with [(11)C]MNPA and [(11)C]raclopride (16 PET measurements with each tracer) at baseline and after pretreatment with various doses of amphetamine. The effect of amphetamine was calculated by the change in binding potential (BP) analyzed with the multilinear reference tissue model (MRTM2). Amphetamine caused a reduction in [(11)C]MNPA BP of 4% at 0.1, 23% at 0.2, 25% at 0.5, and 46% at 1.0 mg/kg. [(11)C]Raclopride BP was reduced to a lesser extent by 2% at 0.1, 16% at 0.2, 15% at 0.5, and 23% at 1.0 mg/kg. The data were used to estimate the in vivo percentage of high-affinity state receptors to be approximately 60%. These results demonstrate that [(11)C]MNPA is more sensitive than [(11)C]raclopride to displacement by endogenous DA, and that it may provide additional information about the functional state of the D(2) receptor in illnesses such as schizophrenia and Parkinson's disease.
Amphetamine↗
Amphetamine-induced dopamine release: duration of action as assessed with the D2/3 receptor agonist radiotracer (-)-N-[(11)C]propyl-norapomorphine ([11C]NPA) in an anesthetized nonhuman primate.
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Amphetamine↗
Serotoninergic neurites in senile plaques in cingulate cortex of aged nonhuman primate.
In immunocytochemical studies, a polyclonal antiserotonin antibody was used to visualize fibers within the cingulate cortex of young and aged rhesus monkeys. Intricate and distinct patterns of serotoninergic processes were seen in anterior and posterior segments of cingulate cortex (Brodmann areas 24 and 23). In these regions of cortex, many multivaricose serotonin-immunoreactive axonal swellings were identified, and some of these immunostained neurites were associated with deposits of amyloid. These observations suggest that serotoninergic processes are involved in the formation of senile plaques in neocortex of aged macaques.
Aging↗
Spontaneous congenital limb malformations in nonhuman primates: a review of the literature.
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Animals↗
Experimental first-trimester amniocentesis in nonhuman primates.
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Amniocentesis↗
Teratogenicity studies on late blighted potatoes in nonhuman primates (Macaca mulatta and Saguinus labiatus).
Female rhesus monkeys and marmosets were fed a diet containing blighted potatoes (Phytophthora infestans) at a level of 10g/kg per day for at least two weeks prior to breeding and six weeks following conception in order to gain additional information on the association of blighted potatoes and the development of anencephaly and spina bifida in primate species. There was an absence of either of these neural-tube defects in 32 rhesus and 14 marmoset infants whose mothers had received a blighted potato diet. In addition there were no cranial osseous defects. There were, however, two rhesus monkey infants with internal hydrocephalus whose mothers had consumed blighted potatoes.
Anencephaly↗
Craniofacial and central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: I. General teratogenicity.
Eighteen pregnant Macaca mulatta, 15 Macaca radiata, and six Papio cynocephalus were treated with 5--20 mg/kg triamcinolone acetonide (TAC) between 21 and 43 days of gestation on single- or multiple-day treatment schedules. Prenatal deaths and stillbirths were tripled in the bonnet monkey and doubled in the rhesus monkey, but did not significantly increase in the baboon. The central nervous system and cranium were the most commonly malformed areas in all three species. The incidence of severe defects, e.g., cranium bifidum, encephalocele, meningocele, and hydrocephalus, was increased in multiple-day treated cases. Minor abnormalities such as aplasia cutis congenita, cranium bifidum occultum, and occipital lobe hypoplasia were more prevalent in single-day treated cases. The sensitive period (days 23--31) for TAC for this group of defects encompasses neural tube closure, rostral demarcation of the midbrain, and development of the primordial collicular plate and two midbrain neuromeres. The results of this study indicate that TAC is a valuable chemical tool for the study of malformations and pathogenesis of the brain and accompanying cranio-facial defects.
Abnormalities, Drug-Induced↗
Craniofacial and central nervous system malformations induced by triamcinolone acetonide in nonhuman primates: II. Craniofacial pathogenesis.
This study further defines the craniofacial malformations induced by triamcinolone acetonide in the rhesus monkey. Ten timed-mated pregnant rhesus monkeys (Macaca mulatta) received intramuscular injections of 10 mg/kg TAC on days 23, 25, 27, 29, and 31 of gestation. Results of previous experiments with rhesus and bonnet monkeys and baboons indicated that specific craniofacial and brain malformations could be induced with TAC during this period of pregnancy (Hendrickx et al., '80). Stage-matched TAC-treated and control embryos (stages 17-18 and 22) and age-matched TAC-treated and control fetuses (50, 60, and 70 days gestation) were removed by hysterotomy. Stage 17-18 TAC embryos appeared grossly normal but histologic evaluation revealed a shortened anlage of the posterior cranial base. Stage 22 TAC embryos and all TAC fetuses exhibited craniofacial dysmorphia and encephalocele. The developing sphenoid was the earliest affected and most severely malformed bone. Its defects included reduced anterioposterior and transverse dimensions, reduced orbitosphenoid and alisphenoid, abnormal pituitary fossa, and reduced dorsum and tuberculum sellae. In addition, shortening of the posterior cranial base and decreased cranial base angle was a consistent finding in the treated embryos and fetuses. Decreased ossification and remodeling in the facial bones and abnormal position due to the malformed sphenoid occurred.
Animals↗
Evaluation of bendectin embryotoxicity in nonhuman primates: I. Ventricular septal defects in prenatal macaques and baboon.
Cynomolgus monkeys, rhesus monkeys and baboons were administered 10 to 40 times the human dose equivalent of Bendectin throughout the major period of organogenesis (22(+/-3)-50 days of gestation). In animals examined prenatally (100 +/- 2 days gestation) the total incidence of ventricular septal defects (VSD) was 40% in cynomolgus monkeys, 18% in rhesus monkeys, and 23% in baboons. The majority of VSD involved the muscular portion of the septum. No dose response was evident and there were no other cardiac or extracardiac defects found except for one baboon fetus with multiple defects. No defects were observed in cynomolgus monkeys administered Bendectin for 4-day periods between 22 and 41 days of gestation. There was no association of Bendectin treatment with any noncardiac defect. In cynomolgus and rhesus monkeys examined at term there was one mitral valve defect and no incidence of VSD. The increased incidence of VSD observed prenatally in all three species and the absence of defects in macaques at term suggests a delay in closure of the ventricular septum in treated animals. The Bendectin-treated monkey may be a suitable model for the study of the pathogenesis of VSD and the mechanism of spontaneous closure of the defect.
Animals↗