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PubMed1993

Measurement of cyclopentenyl cytosine 5'-triphosphate in vitro and in vivo by multidimensional high-performance liquid chromatography.

Cyclopentenyl cytosine 5'-triphosphate (CPEC-TP) is the active metabolite of the investigational drug cyclopentenyl cytosine (CPEC), a nucleoside analogue which exhibits noteworthy antineoplastic activity against several murine and human tumors in tissue culture, and which is now undergoing Phase I clinical trials. This study describes a method to measure the intracellular CPEC-TP levels in peripheral blood mononuclear cells (PBM cells) from patients treated with CPEC, without using radiolabeled drug. The method utilizes on-line multidimensional high-performance liquid chromatography (HPLC) with two columns of different retention mechanisms connected via an automated programmable switching valve. The elution fraction containing CPEC-TP is initially separated from cellular components using a gel sizing column (TSK-G2000-SW) and then rechromatographed by means of a reversed-phase column operated in an ion-pairing mode (YMC-A-312-ODS). The limit of quantitation of CPEC-TP by this method is 2.5 pmol per injection. When CPEC-TP levels were measured in PBM cells from 12 cancer patients after 20 h continuous infusion of CPEC at doses ranging from 3.5 to 5.9 mg/m2/h, the levels attained ranged from 1.4 to 13.4 microM (3.6 to 33.5 pmol/10(7) cells). However, wide variability in the concentrations of CPEC-TP achieved were evident at each dose and did not appear to correlate either with the CPEC dose or with CPEC plasma levels. This method was validated by a comparison of the quantitation of CPEC-TP in cultured PBM cells and Molt-4 cells (a human T-cell line adapted for growth in tissue culture) after incubation with both unlabeled and radiolabeled CPEC.

Animals↗
PubMed2000

Potential of ribozymes against deoxycytidine kinase to confer drug resistance to cytosine nucleoside analogs.

Hematopoietic toxicity is the dose-limiting side effect produced in cancer chemotherapy with deoxycytidine nucleoside analogs. Deletion of the deoxycytidine kinase (dCK), results in a drug resistance phenotype to these analogs. An interesting gene therapy strategy to confer drug resistance to cytosine nucleoside analogs would be to specifically inactivate the dCK in normal hematopoietic stem cell. In this study, we designed hammerhead ribozymes that can specifically cut and downregulate the murine dCK mRNA. Three different ribozymes were identified and shown to cleave in vitro the dCK RNA. After introduction of ribozyme cDNA into murine L1210 leukemic cells by retroviral transfer, two of the ribozymes showed some capacity in reducing dCK activity. However, analysis of transduced L1210 clones showed that the significant reduction in the dCK mRNA was not sufficient to confer drug resistance to cytosine arabinoside. Nevertheless, these results provide a new avenue of modulating the dCK enzyme activity and with improved modifications may have the potential for use in gene therapy to confer drug resistance to deoxycytidine analogs.

Animals↗
PubMed1990

Mitoxantrone, cytosine arabinoside, and VP-16 in 36 patients with relapsed and refractory acute myeloid leukemia.

Mitoxantrone in combination with VP-16 proved to be effective in refractory and relapsed acute myeloid leukemia (AML), with 42% of patients achieving complete remission (CR). The aim of this study was to assess whether the addition of cytosine arabinoside increased the response rate at a tolerable toxicity. The regimen consisted of mitoxantrone (M) 10 mg/m2 i.v. days 4-8, cytosine arabinoside (A) 100 mg/m2 continuous infusion days 1-8, and etoposide (VP-16) (V) 100-120 mg/m2 i.v. days 4-8 (MAV protocol) for relapsed and refractory AML. Thirty-six patients were treated, with a median age of 51 (20-73) years. For induction therapy one to two MAV cycles and for consolidation therapy two courses were scheduled. Twenty-one (58.3%) patients attained a complete remission (CR), with a median duration of 4.5 (1-12+) months. The median survival of all patients was 5.5 (0.5-15.5+) months. Four patients died in CR from chronic infections or after consolidation therapy with MAV. In evaluable patients, times to greater than 500 granulocytes/microliters and greater than 25,000 platelets/microliters were 23 (7-46) and 23 (6-44) days, respectively. In 54 evaluable MAV courses the following toxicity was observed (WHO grades 3/4): 26%, nausea and vomiting: 9%, hemorrhage; 6%, bilirubinemia; 11%, diarrhea; 22%, mucositis; 6%, local infection; 20%, septicemia; 13%, fever of unknown origin; 2%, cardiac arrhythmia; 7%, congestive heart failure. We conclude that MAV therapy is a highly active antileukemic combination with acceptable toxicity, which is recommended for further clinical trials in untreated AML.

Adult↗
PubMed1989

Daunomycin, cytosin-arabinoside and VP-16 (DAV) for myeloid blast crisis of CML.

Nine patients with myeloid blast crisis of Philadelphia chromosome-positive chronic myelocytic leukemia received 1-3 courses of intensive induction chemotherapy with DAT (daunomycin, cytosin-arabinoside and 6-thioguanin) or DAV (daunomycin, cytosin-arabinoside and VP-16). Eight patients responded with clearing of blasts from peripheral blood giving a response rate of 89%. However, bone marrow aplasia with less than 5% blasts was seen in only 2 patients. These 2 patients subsequently received an allogeneic bone marrow transplant and achieved complete remissions of 3 and 6 month duration. All patients died due to progression of blast crisis. Median survival of the group was 164 days. These results were compared to a historical control group of 31 patients with myeloid blast crisis treated with vincristine and prednisone. Despite a significantly better response rate with DAV or DAT (8 of 9 versus 9 of 31, p = 0.01) survival was not significantly different than that of the control group.

Adult↗
PubMed1991

Salvage chemotherapy containing moderate-dose cytosine arabinoside and mitoxantrone for relapsed and resistant acute myeloid leukaemia.

A total of 29 evaluable patients with acute myeloid leukaemia (AML) either in relapse or resistant to initial induction daunorubicin-containing chemotherapy were given a salvage regimen consisting of moderate-dose cytosine arabinoside and mitoxantrone. There were 8 (28%) complete responders (CRs), 4 (14%) partial responders (PRs), and 17 (52%) nonresponders. The duration of CRs was 2+, 2+, 3+, 3, 4+, 4, 5 and 6 months respectively. Two of the eight CR patients were refractory to initial daunorubicin-containing induction therapy and another two had achieved a previous CR lasting less than 6 months. Four of the eight CR patients had received an amsacrine-containing salvage regimen (ATA) prior to administration of the present moderate-dose cytosine arabinoside and mitoxantrone regimen; this indicates the lack of absolute clinical cross-resistance between the present combination and the daunorubicin- or amsacrine-containing regimens. However, the duration of CRs achieved by these patients remains very short and should, if possible, be followed by allogeneic or autologous bone marrow transplantation.

Acute Disease↗
PubMed1993

Cytosine arabinoside increases the binding of 125I-labelled epidermal growth factor and 125I-transferrin and enhances the in vitro targeting of human tumour cells with anti-(growth factor receptor) mAb.

We report that cytosine arabinoside (Ara-C), a cytosine analogue that at low doses causes phenotypical changes on human leukemia cells in vitro and in vivo, induces growth inhibition of oropharyngeal cancer KB and lung adenocarcinoma A549 cell lines. An increase in the number of epidermal growth factor and transferrin receptors (EGFR, TrfR) is induced by Ara-C on these cells. Maximal EGFR up-regulation occurs 96 h after the beginning of Ara-C exposure while maximal TrfR up-regulation is detected 24 h later. These effects occur without changes in the affinity of EGFR and TrfR for their ligands. Two classes of EGF-binding sites with a Kd of 0.055 nM and 2.3 nM respectively, and one class of transferrin-binding sites with a Kd of about 4 nM are detected on both untreated and Ara-C-treated KB cells. [3H]Thymidine uptake is clearly stimulated on KB cells by nanomolar concentrations of EGF and transferrin, whereas in Ara-C-treated cells [3H]thymidine uptake is not increased by EGF and transferrin under conditions where maximal EGFR and TrfR up-regulation occurs. The enhanced EGF and transferrin binding is paralleled by a twofold increase of in vitro targeting of Ara-C-treated KB and A549 cells with anti-EGFR 108.1 mAb and anti-TrfR OKT9 mAb. We propose that Ara-C could provide a new approach for the improvement of the therapeutic index of anti-EGFR and anti-TrfR immunoconjugates.

Adenocarcinoma↗
PubMed1984

Effect of D-valine and cytosine arabinoside on [3H]thymidine incorporation in rat and rabbit epididymal epithelial cell cultures.

Epithelial cell enriched primary cultures were established from the rat and the rabbit epididymis. Epithelial cell aggregates, obtained after pronase digestion of minced epididymis, attached to the culture dish and after 72 h in vitro spread out to form discrete patches of cells. These cells have an epithelioid morphology and form a monolayer of closely apposed polygonal cells where DNA synthesis, as judged by [3H]thymidine uptake, is very low. In L-valine medium the nonepithelial cell contamination was no more than 10% in rat and rabbit epididymal primary cultures. The labeling index of rat epididymal cells cultured in D-valine medium was significantly lower than that of cells cultured in L-valine medium. In contrast, the labeling index of rabbit epididymal cells cultured in D-valine medium was significantly higher than that of cells cultured in L-valine medium. Cytosine arabinoside decreased the number of labeled cells in both L-valine and D-valine cultures. From these results, it appears that D-valine is a selective agent for rat epididymal epithelial cells, but not for rabbit epithelial cells, and that cytosine arabinoside is a simple and effective means to control the proliferation of fibroblast-like cells in both rat and rabbit epididymal cell cultures.

Animals↗
PubMed1985

Effects of cytosine arabinoside on DNA synthesis and mitotic activity of HL-60 cells.

HL-60 cells were exposed to tritiated thymidine (3HTdR) alone (control group), to cytosine arabinoside followed by 3HTdR or to tritium labelled cytosine arabinoside (3H-AraC) for one hour followed by incubation with colcemide to arrest them during metaphase. Autoradiographic slides were prepared and cell counts were at 1, 24, 48 and 72 h. The studies demonstrated that HL-60 cells exposed to high concentrations of AraC (10 micrograms ml-1) can pass through the S-phase as the G2-phase of the cell cycle and enter mitosis. Despite completing the S-phase, the cells exposed to AraC were severely damaged and had already begun to die.

Autoradiography↗
PubMed1992

Cytosine arabinoside and etoposide (CARE) in relapsed and refractory non-Hodgkin's lymphoma.

Twelve patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with a 5 day protocol of high dose cytosine arabinoside 3 g/m2 and etoposide 200 mg/m2 (CARE) daily for 4 days for either 1 or 2 cycles together with alternating intrathecal cytosine arabinoside and methotrexate. Seven men and 5 women aged 18 to 65 years (median age 47.5 years) have received a total of 19 cycles. Six patients had Stage III and 6 had Stage IV disease, all with marrow involvement. Three patients had diffuse small lymphocytic NHL, 3 had diffuse large cell NHL, 3 had diffuse small cleaved NHL and 3 remaining patients had diffuse mixed small and large cell NHL, lymphoblastic NHL and Burkitt's. Six patients (50%) achieved complete remission (3-44 months), four of whom subsequently underwent successful autologous bone marrow transplantation and a fifth has had marrow harvested in preparation for ABMT. One patient achieved partial remission and 5 patients had no response to CARE. Ten patients had nadir granulocyte counts less than 0.5 x 10(9)/l and all required red cell (range 2-11 units) and platelet (range 6-130 units) transfusions. The platelet nadir was less than 20 x 10(9)/l in all patients. One patient with refractory disease succumbed to pulmonary haemorrhage while three other patients developed reversible toxicity with serve mucositis, prolonged diarrhoea and acute renal failure. One patient with refractory disease died with a progressive neuropathy.

Adolescent↗
PubMed2002

Cytosine-phosphate-guanine (CpG) motifs are sensitizing agents for lipopolysaccharide in toxic shock model.

OBJECTIVE: Unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides are highly frequent motifs in bacterial DNA and rare in the mammalian genome. They are potent inducers of inflammatory cytokines and act synergistically with lipopolysaccharide (LPS) for the induction of tumor necrosis factor alpha (TNF-alpha) production in vivo. It has therefore been suggested that innate immune reaction to bacterial unmethylated CpG motifs might contribute to the development of septic shock. We designed this study to assess the sensitization role of CpG motifs in LPS-induced shock using the D-galactosamine (D-GalN)-sensitized mouse model. DESIGN: A prospective, randomized in vivo animal laboratory study. SETTING: Experimental research laboratory. INTERVENTION: We performed experiments in which CpG, LPS and D-GalN were administrated sequentially in various orders or simultaneously in 8 week-old BALB/c mice. MEASUREMENTS AND RESULTS: Cytosine-phosphate-guanine treatment potentiated LPS action only if injected prior to LPS. A combination of predefined sublethal doses of CpG (1 nmol/mouse) and LPS (1 ng/mouse) not only had a synergetic effect on TNF-alpha production (20.3+/-9.2 IU/ml versus 2.5+/-1.4 IU/ml and 5.6+/-3.4 IU/ml for CpG and LPS groups, respectively, p<0.05), but also led to animal death (5/5). An CpG effect requires de novo mRNA synthesis, since the sensitizing effect was inhibited by co-administration of mRNA transcription inhibitors such as D-GalN and pentoxifylline, which is a specific TNF-alpha transcription inhibitor. Furthermore, CpG treatment provoked a strong TNF-alpha mRNA production in the liver that was dramatically reduced by pre-treatment with D-GalN. CONCLUSION: Our findings indicate that CpG motifs act synergistically with LPS by initializing the synthesis of TNF-alpha and/or TNF-alpha regulating factors, thereby acting as a sensitizing agent.

Animals↗
PubMed2000

Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer.

PURPOSE: To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer. METHODS: Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF). RESULTS: Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5-58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69+/-6.30 mM (SD). The half life for elimination was 1.45+/-0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments. CONCLUSIONS: IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.

Adult↗
PubMed1999

Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil.

The antitumor ribonucleoside analogues 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)uracil (EUrd), first synthesized in 1995, have strong antitumor activity against human cancer xenografts without severe side effects. Here, we studied the antitumor mechanisms of ECyd and EUrd using mouse mammary tumor FM3A cells in vitro and the mechanism of selective cytotoxicity of ECyd using human tumor xenografts in nude rats in vivo. In FM3A cells, ECyd and EUrd were rapidly phosphorylated to ECyd 5'-triphosphate (ECTP) and EUrd 5'-triphosphate (EUTP), which strongly inhibiting RNA synthesis. Cells treated with EUrd were later found to contain both EUTP and ECTP, and ECTP accumulated as the final product. Probably the uracil moieties of EUrd derivatives were efficiently converted to cytosine moieties in the cells. EUrd and its derivatives were minor metabolites in the cells treated with ECyd, so cytidine forms probably were not converted to uridine forms at the nucleoside or nucleotide stage. The ultimate metabolite of ECyd and EUrd, ECTP, is stable in cultured cells with a half-life of at least 3 days, so ECyd and EUrd are on a "closed" metabolic pathway to ECTP. These characteristics of ECyd and EUrd may be important for their antitumor activity. ECyd had strong and selective antitumor activity against the human tumor xenografts. ECyd-phosphorylating activity (uridine/cytidine kinase) in the xenografts was higher than that in the organs of the rats. This finding may account for the strong activity with mild side effects. ECyd and EUrd may be a new kind of antitumor nucleoside analogue for clinical use.

Animals↗
PubMed1981

Ara-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia.

Unexplained fatal pulmonary edema observed at autopsy in leukemic patients treated with cytosine arabinoside (Ara-C) suggested a possible role of the drug in causing increased alveolar capillary permeability. We reviewed clinical and pathologic features of the 181 patients with leukemia who were examined at autopsy at The Johns Hopkins Hospital in the past 12 years, 93 (51 percent) of whom had received intravenous Ara-C in doses of 7.5 to 30 mg/kg/day (average dose, 16 mg/kg/day). Fifty-one patients had received their last treatment within 30 days, and 42 patients between 31 and 894 days, prior to death. Among the 181 patients examined at autopsy 43 (24 percent) had massive edema, 59 (33 percent) had moderate edema, and 79 (44 percent) had either slight edema or no pulmonary edema. The 51 patients who had received Ara-C within 30 days of their death, compared to the other 130, had a highly significant increase in the frequency of pulmonary edema (p less than 0.001), which was massive in 24 and moderate in 18. In these 42 patients, causative or contributing factors that explained the edema were present in 14 (33 percent) of them, but in 28 (67 percent) there was no apparent explanation. In contrast, 60 of the 130 patients who had no or remote Ara-C therapy had massive (19 patients) or moderate (41 patients) pulmonary edema, which was explained in 55 (92 percent) and unexplained in only five (8 percent) (p less than 0.001). The unexplained pulmonary edema, a highly proteinaceous interstitial and intra-alveolar infiltrate, correlated with gastrointestinal lesions typical of Ara-C toxicity (p less than 0.001). Multivariate regression analysis showed that unexplained pulmonary edema was predicted by the recent administration of Ara-C, but by no other chemotherapeutic agent, including daunomycin, a potential cardiotoxin frequently given in conjunction with Ara-C. The study suggests that increased alveolar capillary permeability may result from the intravenous administration of cytosine arabinoside and that this complication should be considered when pulmonary edema develops in leukemic patients treated with Ara-C.

Adolescent↗
PubMed1984

High-dose cytosine arabinoside. Active agent in treatment of non-Hodgkin's lymphoma.

Seventeen extensively pre-treated patients with non-Hodgkin's lymphoma in relapse were treated with high-dose cytosine arabinoside given at a dose of 3 g/m2 on a 12-hour basis for two to eight doses per course. Seventy percent of patients (12 of 17) showed response with this regimen, including three patients who achieved a complete response. The time to response was quite rapid, occurring between three and 14 days, with median duration of complete responses of 12 weeks and of all responses, five weeks. Toxicity was acceptable, including predictable myelosuppression and thrombocytopenia, occasional drug fever, infrequent conjunctivitis and dermatitis, and no central nervous system toxicity. The dramatic, albeit short-lived, responses to high-dose cytosine arabinoside in this refractory population suggest that it is an active agent against non-Hodgkin's lymphoma and should be further evaluated.

Adult↗
PubMed1993

Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts.

Cyclopentenyl cytosine (CPE-C), a carbocyclic analogue of cytidine, has preclinical antineoplastic activity against ara-C resistant murine leukemias and a broad spectrum of human tumor xenografts. CPE-C is a prodrug and requires intracellular phosphorylation to cyclopentenyl cytosine triphosphate (CPE-CTP) which depletes endogenous CTP pools. The initial step in this activation process is catalyzed by uridine/cytidine kinase. We studied the mechanism of resistance to CPE-C in a Molt-4 T-cell leukemia line made resistant to CPE-C (Molt-4R) by culturing it in the continuous presence of increasing concentrations of CPE-C. Using a tetrazolium based colorimetric assay to assess cytotoxicity, the IC90 for the parent Molt-4 cells (Molt-4WT) was 0.5 microM after a 24 hr drug exposure. In contrast, cytotoxicity was not observed at concentrations as high as 1 mM in the Molt-4R cells. Following a brief exposure to 1 microM CPE-C, parent drug could be detected intracellularly in the resistant and sensitive cell lines. However, CPE-CTP formation was reduced markedly in the resistant cell line. Measurement of the activity of anabolic and catabolic enzymes in the Molt-4WT and Molt-4R cells revealed equivalent activities of alkaline and acid phosphatases as well as cytidine and dCMP deaminase but there was a significant reduction in uridine/cytidine kinase activity in Molt-4R cells. Endogenous ribonucleotide pools and CPE-CTP pools were measured in the absence and presence of CPE-C. CTP pools were reduced markedly in Molt-4WT cells following exposure to CPE-C. However, CTP pools in Molt-4R cells exposed to 100 microM CPE-C were two times greater than in the untreated Molt-4WT cells. At high concentrations of CPE-C (10 and 100 microM), Molt-4R cells were able to generate amounts of CPE-CTP equivalent to that seen in Molt-4WT cells exposed to 1 microM CPE-C (a cytotoxic concentration of drug in Molt-4WT cells), but no cytotoxic effect was seen in Molt-4R cells. Therefore, in addition to decreased uridine/cytidine kinase activity, a second mechanism of resistance that is the result of alterations in CTP synthetase activity also appears to be operative. Elucidation of the mechanism of resistance in vitro may provide insight into the mechanism of action of the drug and potential mechanisms of resistance in vivo.

Antineoplastic Agents↗
PubMed1976

Arapen: a secondary complex between platinum ethylenediamine dichloride and cytosine arabinoside. I. Preparations and reactivity towards nucleic acid constituents.

An equimolecular complex between platinum ethylenediamine dichloride (PtenCl2) and 1-beta-D-arabinofuranosyl cytosine (araC) has been prepared (arapen). This 1 : 1 complex in which both ethylenediamine and araC moieties carried a radioactive label was found to be unreactive towards cytosine and guanine derivatives, but to react to the extent of 30% with deoxyadenosine, adenosine 5' -monophosphate, polyadenylic acid, poly a(AT) and DNA at comparable rates. It is suggested that adenine compounds react with platinum complexes such as PtenCl2 in a bidentate manner, but are still able to react with arapen as monodentate ligands. However, hydrolysis of the last chloride ion from arapen may not be complete, and the incoming adenine nucleophile is only able to react to a limited extent.

Binding Sites↗
PubMed1985

Triethanolamine, tris, hepes, and cytosine arabinoside show neuritogenic activity in cultured chick embryo ganglia.

Neuritogenesis, which occurs to a slight extent in chick embryo ganglia maintained under standard conditions and which is maximally stimulated by nerve growth factor, also was enhanced by presence in the medium of buffers (triethanolamine, Tris, and Hepes) and cytosine arabinoside and by the passage of direct electric current. The major effect of the buffers probably was to remove protons from cell membranes, that of the current to produce accelerated movement of ions through membranes of the ganglionic cells, and that of cytosine arabinoside to decrease the numbers of nonneural cells by inhibiting DNA synthesis. The buffers were neuritogenically ineffective on nerve growth factor-sensitive PC12 pheochromocytoma cells in culture. Media from ganglia in which triethanolamine or passage of electric current had elicited outgrowth of neurites produced no observable effect on PC12 cells under our experimental conditions. Current data fit the hypothesis that, whereas nerve growth factor exerts direct neuritogenic effects on neurons, the other treatments affect neural-nonneural interactions, possibly by way of gap junctions or changes in direct physical contact, so as to disinhibit inherent neural neuritogenic potential and/or to stimulate it.

Animals↗
PubMed1986

Effect of cytosine arabinoside on the composition of the nonneuronal cell population in cerebral explants.

Rat cortical explants were cultured in the presence or absence of the mitotic inhibitor cytosine arabinoside to determine whether or not it affects the composition of the nonneuronal cell population within the outgrowth zone. Ultrastructural morphometric analysis of the incidence of fibroblasts, fibrous astrocytes, and protoplasmic astrocytes-epithelial cells at 18 days in vitro, revealed statistically significant decreases in the incidence of fibroblasts and fibrous astrocytes in the explants treated with the inhibitor compared with control explants. Coupled with earlier findings of enhanced neurite outgrowth and decreased nonneuronal cell proliferation that follows such treatment, it appears that cytosine arabinoside may potentiate neurite outgrowth by altering the composition, as well as the number, of nonneuronal cells in the outgrowth zone. These data indicate that fibroblasts and fibrous astrocytes may limit the regenerative response of severed axons in the mammalian central nervous system.

Animals↗