Injection Of Cytosine Arabinoside Research Articles

Essence of Alpha Male

Pheromones are chemicals involved in mating and reproduction. In rodents, these chemicals are detected by the vomeronasal organ, which humans lack, and by the olfactory system. Mate-specific pheromone memories play an important role in female rodent reproduction. Two parts of the brain that undergo neurogenesis in the adult are the olfactory bulb (the new neurons originate in the subventricular zone) and the dentate gyrus of the hippocampus. In rodents, neurogenesis in the olfactory bulb is stimulated by mating or pregnancy. Neurogenesis in the hippocampus is stimulated by running, enriched environments, or learning. Mak et al . found that pheromones in the urine of dominant, but not subordinate or castrated, male mice stimulated the neurogenesis of both the olfactory bulb and the dentate gyrus in female mice. Furthermore, females exposed to dominant-male pheromones and then presented with both a dominant and a subordinate male spent more time sniffing the dominant male's compartment, indicating preference for the dominant male. This pheromone-induced male preference was lost if the female mice were deficient in the prolactin receptor (PRLR) or if neurogenesis was blocked by injection of cytosine arabinoside. It is known that male pheromones trigger surges in luteinizing hormone (LH) and prolactin (PRL) in the female mice. Mak et al . detected PRLR in the subventricular zone (the source of the new olfactory bulb neurons) and detected the LH receptor in both the subventricular zone and the dentate gyrus. Injection of low doses of LH stimulated neurogenesis in the dentate gyrus, whereas injection of PRL stimulated neurogenesis in the subventricular zone. Male pheromones failed to stimulate subventricular zone neurogenesis in the female mice deficient for the PRL receptor, and neurogenesis in the dentate gyrus was absent in the mice deficient for the LH receptor. These results raise the question of whether male pheromones contribute to human mate selection, and undoubtedly the perfume industry will be keenly interested in whether they can create the "dominant-male fragrance" (see commentary by DiRocco and Xia). G. K. Mak, E. K. Enwere, C. Gregg, T. Pakarainen, M. Poutanen, I. Huhtaniemi, S. Weiss, Male pheromone-stimulated neurogenesis in the adult female brain: Possible role in mating behavior. Nat. Neurosci. 10 , 1003-1011 (2007). [PubMed] D. P. DiRocco, Z. Xia, Alpha males win again. Nat. Neurosci. 10 , 938-940 (2007). [PubMed]

Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation.

Angiotensin I-converting enzyme (ACE) has been shown to be involved in the catabolism of the tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP). As AcSDKP is a physiological inhibitor of haematopoietic stem cell proliferation, we investigated the in vitro and in vivo effects of captopril, one of the specific inhibitors of ACE, on the proliferation of primitive haematopoietic cells. Regenerating bone marrow cells obtained from mice given one injection of cytosine arabinoside (100 mg/kg) as well as SA2 myeloid leukaemia cells were incubated in vitro for 24 h with 10-6 M captopril. Captopril significantly reduced the proportion of high proliferative potential colony-forming cells (HPP-CFC-1) in S-phase, whereas it had no effect on the proportion of SA2 leukaemic colony-forming cells in S-phase. When given in vivo to mice 1 h after 2 Gy gamma-irradiation or cytosine arabinoside (AraC) injection, captopril (100 mg/kg) was shown to prevent HPP-CFC-1 entry into S-phase induced by these cytotoxic treatments. The observed effects correlated with a reduction in ACE degradative activity and an increase in the level of endogenous AcSDKP both in the supernatants of captopril-treated bone marrow cells and in plasma of treated animals. The present findings suggest that AcSDKP might mediate the observed in vitro and in vivo inhibitory effects of captopril on primitive haematopoietic cell proliferation.

Further evidence for supporting cell conversion in the damaged avian basilar papilla

Two lines of evidence suggested that a process other than supporting cell divisions may give rise to new hair cells in the bird inner ear injured by either noise or ototoxic drugs. This process, supporting cell conversion, occurs when non-dividing supporting cells transdifferentiate into hair cells. First, noise-exposed chicks received zero, one or two daily i.p. injections of cytosine arabinoside (a DNA synthesis blocker), as well as two daily intraperitoneal injections of bromodeoxyuridine, for four days. Following sacrifice, the papillae were processed for bromodeoxyuridine immunocytochemistry. All the ears demonstrated dividing cells, but increasing the number of cytosine arabinoside injections decreased the number of labeled cells. Indeed, two cytosine arabinoside injections per day nearly completely blocked supporting cell divisions in the short hair cell region within the sound-induced lesion. This suggested that unpaired, immature cells observed in a similar region with scanning electron microscopy, despite the presence of cytosine arabinoside, may have been products of supporting cell conversion. In the second experiment, birds were treated with gentamicin for three days. Upon sacrifice at 6 days post-treatment, papillae were processed for light and transmission electron microscopy. Several unusual cells were observed with phenotypic features of both hair cells and supporting cells. The peculiar cells may be in a transition from the supporting cell phenotype to that of a hair cell.

Serotonin metabolism in the CNS in cerebellar ataxic mice

The metabolism of 5-hydroxytryptamine (5-HT) in the CNS was investigated in four kinds of morphologically different ataxic mice; reeler, staggerer, weaver and Purkinje cell degeneration mutants, and in hypocerebellar mice experimentally produced by injection of cytosine arabinoside. 5-HT and 5-hydroxyidoleacetic acid concentrations and tryptophan hydroxylase (TrpOH) activity were measured in the cerebrum, cerebellum and brain stem, respectively. TrpOH activity was significantly reduced only in the reeler mouse. The enhancements of the cerebellar 5-HT metabolism observed in the ataxic mice other than the reeler were supposed to be pseudo-enhancements subsequent to the cerebellar hypoplasia.

The pathogenesis of abnormal cytoarchitecture in the cerebral cortex and hippocampus of the mouse treated transplacentally with cytosine arabinoside.

Pregnant mice were treated with cytosine arabinoside on days 13.5 and 14.5 of pregnancy. Brains of the offspring were studied histologically. The matrix layer of the embryonic brains was extensively destroyed 12 h after the injection of cytosine arabinoside, but regenerated partially on day 17 of gestation. In the cerebral cortex of 1-, 3-, and 5-day-old treated mice, abnormal clusters of young neurons were found on the surface of the developing cerebral cortex. Some clusters still had a supply of immature neurons from the remnants of the regenerated matrix layer. After 20 days, the clusters became gradually indistinct, although some vestigial groups of neurons were observed even after 120 days. In the hippocampus of young mice, the pyramidal cells decreased in number and were disarranged. Heterotopic pyramidal cell masses were found in the stratum radiatum and in the molecular layer of the dentate gyrus. Apical dendrites of pyramidal cells exhibited abnormal arborization. It was demonstrated by 3H-thymidine autoradiography that young neurons in the abnormal clusters in the cerebral cortex were those produced in the matrix layer regenerated after the destructive change by cytosine arabinoside.

The effect of a single injection of cytosine arabinoside on cell population kinetics in the mouse jejunal crypt.

The early effects of a single injection of cytosine arabinoside (ara-C) on cell population kinetics in the jejunal crypt of the mouse were studied using autoradiography with tritiated thymidine, and metaphase arrest with vincristine. Ara-C had three main effects on crypt cells: a block of cells near the transition from G1 to S, death of nearly all cells in S, and a temporary block of the survivors, which remained viable and were able to proceed through the cell cycle. Throughout the crypt there was a decrease in cell cycle time and an increase in growth fraction. Although changes in proliferative rate were highest in the lowest part of the crypt it was not possible to show that crypt repopulation originated only from basal crypt cells, and the data are consistent with repopulation from the faster cycling cells in the proliferative compartment.

Improved immune-suppression techniques for the xenografting of human tumours

The transplantability of a xenografted human adenocarcinoma has been examined in mice that had been immune-suppressed by thymectomy and whole-body irradiation and the results have been compared with transplantation into athymic (nude) mice. Two alternative techniques were used to prevent marrow failure following whole-body irradiation: reconstituting the animals with a marrow graft, or protecting them by an injection of cytosine arabinoside (Ara-C) 2 days before the irradiation. The results show that the Ara-C-prepared mice were more receptive to transplantation than marrow-grafted or nude mice, and they were the only animals that developed regional metastases from implanted xenografts. Some recovery of immunity occurred in both types of immune-suppressed mice, which was evident more than 5 weeks after immune-suppression and which was more marked in females than in males. It was concluded that the immune-suppressed mice were superior to nude mice for short-term experiments but they may be less satisfactory for long-term experiments.

Cell Proliferation and Protein Synthesis in Human Leukaemic Myeloblasts after Cytosine Arabinoside Therapy

The effect of a single intravenous bolus injection of cytosine arabinoside (ARA-C) on the cytokinetics and 3H-leucine uptake of leukaemic myeloblasts in bone marrow and blood was studied at intervals up to 96 h after ARA-C in five patients with previously untreated acute myelogenous leukaemia. An early decrease in mitotic index and in 3H-thymidine labelling was observed in four of five patients and pretreatment values were reached again within the observation period. Changes suggesting synchronization were not observed. ARA-C induced a marked decrease in protein synthesis in the leukaemic myeloblasts as estimated from either a decrease in the 3H-leucine labelling index or the mean grain count of 3H-leucine labelled cells. It is suggested that ARA-C is incorporated also by cell which are not in S-phase and has a prolonged biochemical effect on the leukaemic cells.

Selective eradication of rat bone marrow erythroid cells by administration of cytosine arabinoside. Observations on resumption phase of erythropoiesis.

The in vivo effect of a single i.p. injection of cytosine arabinoside (250 mg/kg body weight) on the rat bone marrow is reported. Cytosine arabinoside (ara-C), a potent inhibitor of DNA-synthesis, was seen to produce selective necrosis of fast cycling bone marrow erythroblasts. The depleted erythroid marrow is replenished by stem cells which are members of the lymphoid-transitional cells compartment. An indirect correlation between the degree of erythroid cell depletion and the extent of marrow lymphocytosis was noted 6-12 h after the administration of ara-C. At 24-48 h, however, the marrow returned to its normal activity. The rat bone marrow 6-12 h following a single injection of ara-C is suggested as an experimental model for providing stem cells committed to the erythroid line.

The Effect of Postirradiation Bleeding or Endotoxin on Proliferation and Differentiation of Hematopoietic Stem Cells

Abstract Bleeding after irradiation failed to affect the time of onset or rate of regeneration of the hematopoietic stem cell compartment as measured by a split-dose irradiation method. Bleeding after a single 600 rad exposure hastened the time of onset of erythropoiesis as measured by spleen colonies and 59Fe uptake, but the early rise was abortive and the second increase began at the same time as the first increase seen in irradiated controls. The largest abortive increase was seen when bleeding occurred within 4 hr of irradiation. Lesser effects were seen when bleeding occurred 12 or 24 hr after and no effect 48 hr after irradiation. A generation time of 6.4 hr for a colony-forming cell that forms a colony in 4 days was calculated from the estimated number of cells in one such colony. Injection of cytosine arabinoside at the time of bleeding reduced colony numbers and 59Fe uptake equally in bled and control mice. Injection of 25 µg Salmonella typhosa endotoxin just after irradiation produced a similar early abortive rise in microscopic granulocytic colonies. These results are compatible with a model for pluripotential stem cell compartment in which: (1) differentiation and self-replication occur concomitantly unless the compartment is reduced below approximately 1O% of normal size; then self-replication occurs without appreciable differentiation; (2) for a short time (∼ 24 hr) after depletion below the threshold, differentiation can occur in response to strong stimuli.