The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats.

Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 µl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed.The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF.

Microfluidic assemblies designed for assessment of drug effects on deformability of human erythrocytes.

Extreme deformability of human erythrocytes is a prerequisite for their ability to squeeze through narrow capillaries of the blood microcirculation system. Various drugs can modify this deformability and consequently provoke circulation problems. We demonstrate that microfluidic assemblies are very convenient platforms for in vitro study of the associated processes. Two types of microfluidic channels were designed to quantitatively investigate modifications of erythrocyte deformability induced by hydrogen peroxide, ethanol and pentoxifylline based on transit velocity measurements. With a high sensitivity our microfluidic assemblies show that hydrogen peroxide decreases erythrocyte deformability in a dose-dependent manner. Then, results on ethanol resolve a biphasic nature of this reactant on the deformability of single erythrocyte cells. Results on pentoxifylline provide evidence that, similar to ethanol, also this medical drug has a double-sided effect on the erythrocyte deformability, i.e. increasing the deformability at low concentrations, while decreasing it at higher ones. Taken together, our microfluidic designs propose a potent measurement method for the erythrocyte deformability, as well as providing a perspective to evaluate effects of drugs on it.

Is there any way to protect from tacrolimus-induced renal and pancreas injury?

BACKGROUND: The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. METHODS: Rats in group I were given saline; rats in group II were injected with tacrolimus; rats in group III were received erythropoietin (Epo) and tacrolimus; while rats in group IV were injected pentoxifylline (Ptx) plus tacrolimus for nine d. On 10th day, blood and tissue samples were taken for biochemical and pathological evaluations. RESULTS: Tacrolimus-injected animals exhibited significant elevation in blood urea nitrogen (BUN), and serum BUN levels were improved in rats pretreated with Ptx. Significantly more apoptotic nuclei were observed in kidneys of tacrolimus group. In rats subjected to tacrolimus and pretreated with Epo, there was significant decrease in apoptotic nuclei staining than those in tacrolimus group. Blood trough levels of tacrolimus were significantly higher in erythropoietin-pretreated group, although same amount of tacrolimus was injected with other groups. CONCLUSION: Results of our study demonstrated significant antiapoptotic effects of erythropoietin on renal tubules, increasing effect of erythropoietin on tacrolimus blood levels, and insignificant antioxidant effects of both erythropoietin and pentoxifylline on renal and pancreas tissues. Study with clinically greater tacrolimus levels may be useful to confirm these findings.

Potentiation of anticancer drugs: effects of pentoxifylline on neoplastic cells.

The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX) on P-gp-mediated multidrug resistance (MDR) in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 µmol/L PTX in the presence or absence of 1.2 µmol/L vincristine (VCR). Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs), especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells.

Efeito de drogas inibidoras de TNF-a em células mononucleares do sangue periférico de pacientes infectados pelo HTLV-I / Effect of drugs inhibiting TNF-a in peripheral blood mononuclear cells of patients infected by HTLV-I

O Retovírus HTLV-I é o agente etiológico da Mielopatia Associada ao HTLV-I/Paraparesia Espástica Tropical (HAM/TSP), Leucemia de Células T do Adulto (ATL) e outras doenças sistêmicas mediadas pela resposta imune. A infecção pelo HTLV-I induz uma elevada proliferação espontânea das células T do perfil de citocinas com predominância das pró-inflamatórias. Nos indivíduos com HAM/TSP o TNF-a encontra-se elevado e envolvido na lesão tecidual. O surgimento de drogas inibidoras da síntese de TNF-a traz a possibilidade de uma terapêutica, buscando reduzir a inflamação e lesão tecidual. O objetivo deste estudo foi avaliar o poder inibidor destas drogas na produção de TNF-a em PBMC de indivíduos infectados com HTLV-I. PBMC de 37 indivíduos foram avaliados: assintomáticos (n=11), subclínicos (n=7) e com mielopatia (n=19). Foram utilizadas quatro drogas inibidoras da síntese de TNF-a: Pentoxifilina, Forskolin, Rolipram e Talidomida, as quais agem em diferentes etapas da síntese desta citocina. As concentrações espontâneas de TNF-a e IFN-y e com as drogas inibidoras foram avaliados nos sobrenadantes das culturas de PBMC através da técnica de ELISA e os resultados comparados entre os grupos usando o teste Mann-Whitney. A produção espontânea de TNF-a foi mais elevada no grupo com HAM/TSP quando comparado ao assintomático e a diferença estatisticamente significante (p = 0.001). A produção espontânea de IFN-y também foi mais alta no grupo com HAM/TSP quando comparados aos assintomáticos e a diferença estatisticamente significante (p = 0.017). Para avaliação das drogas inibidoras de TNF-a, utilizamos PBMC de indivíduos com de TNF-a e IFN-y espontâneos maiores que 5 pg/ml e os resultados comparados pelo teste estatístico Wilcoxon signed ranks. Pentoxifilina foi utilizada nas doses de 50 e 200 μM. A inibição da produção de TNF-a com 50 μM foi de 71 ± 26% (p = 0.003) e de IFN-y com 50 μM foi de 46 ± 24% (p = 0.001). Forskolin foi utilizado nas doses...

Pentoxifylline diminished acetaldehyde-induced collagen production in hepatic stellate cells by decreasing interleukin-6 expression.

The effect of pentoxifylline (PTX), a methylxanthine derivative, on collagen induction and secretion and on the production of mRNA of two fibrogenic cytokines: interleukin-6 and transforming growth factor-beta(1) (IL-6 and TGF-beta(1)) in a rat hepatic stellate cell line (CFSC-2G) exposed to acetaldehyde was studied. CFSC-2G cells were treated with 175 microM acetaldehyde for 24h. The cells were then exposed to a medium containing 200 microM PTX. Collagen secretion, increased 2.6 times in acetaldehyde treated cells. Cells exposed to acetaldehyde and treated with PTX diminished collagen secretion to control values and decreased alpha(1)(I) collagen mRNA by 15%. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays of TGF-beta(1) mRNA showed no variation in different experimental conditions. However, PTX induced a decrease of 32% in IL-6 mRNA in acetaldehyde-treated cells. CFSC-2G cells treated with anti-IL-6 monoclonal antibody, 15min before acetaldehyde was added, did not present an increase in alpha(1)(I) collagen mRNA. These results show that PTX inhibits the expression of alpha(1)(I) collagen via the inhibition of IL-6 in acetaldehyde treated cells. The effect herein reported on IL-6 and alpha(1)(I) collagen mRNA adds to the previously described effect of PTX, which could be useful in the fibrogenic process induced by acetaldehyde.

Effects of pentoxifylline on inflammatory cytokine expression and acute pleuropneumonia in swine.

Pentoxifylline, a methylxanthine derivative and nonspecific type 4 phosphodiesterase inhibitor, has been used to improve survival of animals with sepsis and to attenuate lung injury in acute lung inflammation. The purpose of this study was to examine whether pentoxifylline would inhibit the expression of inflammatory cytokines, particularly tumor necrosis factor alpha (TNF), and thereby decrease the pathophysiology of acute porcine pleuropneumonia. E. coli lipopolysaccharide (LPS) and bacterial extracts of A. pleuropneumoniae--induced elevations in TNF mRNA which were fully abrogated by addition of pentoxifylline in both alveolar macrophage and neutrophil cultures. A 30% reduction in the level of LPS-induced interleukin (IL)-1beta mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL-1alpha or IL-8 expression in vitro. Pentoxifylline therapy in vivo significantly reduced the number of band neutrophils in swine but did not reduce the pathology associated with pleuropneumonia, including changes in serum zinc, iron, or haptoglobin. Neither did it alter TNF, IL-1, IL-6, or IL-8 expression. Measurement of pentoxifylline and its metabolites in pig sera suggested that efficacious doses of pentoxifylline were probably not achieved in vivo. However, subcutaneous doses of pentoxifylline higher than 25 mg/kg produced transient diarrhea, vomiting, and tremors. These results suggest that pentoxifylline is an effective pharmacological tool for the dissection of cytokine regulation in vitro, but inhibitory concentrations may not be achievable for in vivo pharmacological use in swine.

Chromosomal aberrations, sister chromatid exchanges and micronuclei induced by pentoxifylline in in vitro cultivated Chinese hamster cells (V79) and human blood lymphocytes.

Pentoxifylline (PTX) is a methylxanthine widely used in clinical practice. The mechanism of PTX effects on cellular and molecular level have not been fully explained yet. The present study was carried out to investigate the cytogenetic effect of this drug using cultured Chinese hamster V79 cells and human blood lymphocytes in vitro. The occurrence of chromosomal aberrations (CA), sister chromatid exchanges (SCE) and micronuclei (MN) was observed after the treatment of cells by different concentrations (0.002-2.0mg/ml) of PTX. In exposed V79 cells and lymphocytes as well, the dose-dependent increases of the above mentioned cytogenetic endpoints were found. The statistically significant increase has appeared at lower PTX concentrations in human lymphocytes than in V79 cells in all the investigated parameters. Our results show that, the applied concentrations of PTX has the clastogenic effect on in vitro cultured V79 cells and human lymphocytes. These findings are notable because of the frequent use of this drug and may serve as preliminary data to the further detailed examination of PTX action on molecular level.

Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology.

It is well established in animal models that production of the cytokine tumour necrosis factor-alpha (TNF-alpha) is essential to the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis. This gives rise to an apparent state of chronic disease which over the next 100-200 days is characterized by slowly worsening pathological changes in the lung. To determine whether continued TNF-alpha production was harmful during this phase mice were treated with a TNF-alpha inhibitor, pentoxifylline. It was observed that although this therapy did not alter the numbers of bacteria recovered from the lungs of the infected mice, tissue damage within the lung was accelerated. These data thus demonstrate that production of TNF-alpha, already known to be important during the early expression of resistance to tuberculosis, remains important and beneficial during the chronic stage of the disease.

Influence of pentoxifylline, A-802710, propentofylline and A-802715 (Hoechst) on the expression of cell cycle blocks and S-phase content after irradiation damage.

The toxicity of the five methylxanthine derivatives, caffeine, pentoxifylline, A802710, propentofylline and A802715, was determined against the two human melanoma lines, Be11 and MeWo, and against the two human squamous cell carcinoma lines, 4197 and 4451, by vital dye staining assay. Pentoxifylline and A802710 emerge as the least toxic showing TD(50) (toxic dose of 50%) levels of 3.0-4.0 mM. Propentofylline and caffeine take an intermediate position. A802715 has a TD(50) of 0.9-1.1 mM and is the most toxic. Subtoxic concentrations (

A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients. The Lisofylline Marrow Transplant Study Group.

The purpose of the study was to evaluate the effect of lisofylline (LSF) on engraftment, regimen-related toxicities (RRT), and mortality in patients undergoing allogeneic bone marrow transplantation (BMT). We performed a multicenter, randomized placebo-controlled trial in 60 patients with hematologic malignancies receiving BMT from HLA-identical sibling donors. Patients were randomized to receive either placebo, 2 mg/kg LSF or 3 mg/kg LSF every 6 h, beginning before conditioning and continuing to day 21 or hospital discharge. Treatment groups were balanced with respect to conditioning regimen and disease stage. However, significantly more patients in the 2 mg/kg LSF group were at high risk for RRT due to performance status >/=1, age >/=40 years, and prior exposure to CMV. Nausea and vomiting were the only adverse events observed in a higher proportion of LSF-treated patients that led to study withdrawal in six of 42 patients (14%). The times to neutrophil recovery to >/=500/microl and platelet recovery (>20 000/microl) were not improved by LSF treatment. Nevertheless, no patient who received treatment with 3 mg/kg LSF developed a documented infection between day 0 and 35 or had a serious or fatal infection between day 0 and 100 (P = 0.003 vs placebo for both). The day-100 survival rate was also significantly improved in the 3 mg/kg LSF group (89%), compared with either the 2 mg/kg LSF (48%) or placebo (61%) groups (log-rank test, 3 mg/kg LSF vs placebo, P = 0. 026). We conclude that treatment with LSF 3 mg/kg reduced the incidence of infections and improved 100-day survival in patients receiving related-donor allogeneic bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 283-291.

Toxicity of pentoxifylline on monolayers of highly proliferative cells of epithelial origin.

Interest in pentoxifylline has been recently reawakened owing to its suppressive effect on cell cytokine production. In this capacity, it may be of value as a routine supplement for culture media containing donor corneas. The purpose of the present study was to evaluate the toxic effects of pentoxifylline on two standardized cell lines of epithelial origin. Vero and Chang cells were incubated with various concentrations of pentoxifylline. Acute toxicity (4 hr) was assessed by monitoring the permeability of cells to propidium iodide; chronic toxicity (7 days) was determined by monitoring the effect of pentoxifylline on esterase activity and cell proliferation. The viability of cells was also assessed by microscopic inspection. Signs of acute toxicity became manifest at a pentoxifylline concentration of 100 mg/l in both Chang and Vero cells. Indications of chronic toxicity were observed at a drug concentration of 10 mg/l in Chang cells but at 1 mg/l in Vero ones. Proliferation was suppressed at pentoxifylline concentrations of 100 mg/l and 10 mg/l in Chang and Vero cells, respectively. Degenerative morphological changes were observed at a drug concentration of 100 mg/l in both cell types. At a concentration of 0.1 mg/l, pentoxifylline elicited no signs of acute or chronic toxicity in either Chang or Vero cells. At this dose, the drug is therefore unlikely to have deleterious effects on cultured donor corneas.

Potentiation of cytotoxicity and radiosensitization of (E)-2-deoxy-2'-(fluoromethylene) cytidine by pentoxifylline in vitro.

(E)-2'-deoxy-2'-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide-diphosphate reductase, has been shown to have anti-tumor activity against solid tumors and sensitize tumor cells to ionizing radiation. Pentoxifylline (PTX) can potentiate the cell killing induced by DNA-damaging agents through abrogation of DNA-damage-dependent G2 checkpoint. We investigated the cytotoxic, radiosensitizing and cell-cycle effects of FMdC and PTX in a human colon-cancer cell line WiDr. PTX at 0.25-1.0 mM enhanced the cytotoxicity of FMdC and lowered the IC50 of FMdC from 79 +/- 0.1 to 31.2 +/- 2.1 nM, as determined by MTT assay. Using clonogenic assay, pre-irradiation exposure of exponentially growing WiDr cells to 30 nM FMdC for 48 hr or post-irradiation to 0.5 to 1.0 mM PTX alone resulted in an increase in radiation-induced cytotoxicity. Moreover, there was a significant change of the radiosensitization if both drugs were combined as compared with the effect of either drug alone. Cell-cycle analysis showed that treatment with nanomolar FMdC resulted in S-phase accumulation and that such an S-phase arrest can be abrogated by PTX. Treatment with FMdC prior to radiation increased post-irradiation-induced G2 arrest, and such G2 accumulation was also abrogated by PTX. These results suggest that pharmacological abrogation of S and G2 checkpoints by PTX may provide an effective strategy for enhancing the cytotoxic and radiosensitizing effects of FMdC.

Inhibition of LPS and Plasmodium falciparum induced cytokine secretion by pentoxifylline and two analogues.

Pentoxifylline and the two analogues HWA138 and HWA448, at concentrations exceeding 60 micrograms/ml, inhibited malaria antigen or lipopolysaccharide (LPS) induced TNF-alpha and IL-1 alpha secretion, but not IL-6 secretion, from human peripheral blood mononuclear cells in vitro. HWA448 had lower inhibitory activity in vitro than pentoxifylline and HWA138. A small enhancement of cytokine secretion was induced by pentoxifylline and the two analogues at low concentrations. The drugs did not affect cell viability. Pentoxifylline, HWA138 and HWA448 also inhibited LPS induced TNF production in vivo in female CF1xBalb/c mice. The drugs were inhibitory at 0.5-1 mg per mouse when mixed with LPS, and 1 mg per mouse of the drugs was inhibitory when injected 1 h before LPS challenge. HWA448 had similar inhibitory activities in vivo compared to pentoxifylline and HWA138, possibly because of the longer serum half-life of HWA448. The pentoxifylline analogues may have lower toxicity than pentoxifylline itself and may therefore be useful in future treatment of diseases induced by endotoxic substances.

Pentoxifylline potentiates the antitumor effect of cisplatin and etoposide on human lung cancer cell lines.

The effect of pentoxifylline (PENT) on the sensitivity of two human lung adenocarcinoma cell lines, PC-9 and PC-14, to cisplatin (CDDP) and etoposide (ET) was studied. PENT at 0.5 and 1 mM enhanced the cytotoxicity of CDDP and ET on PC-14 and PC-9, respectively. Isobologram analyses of IC50 data, as well as combination index calculations, revealed that PENT had an additive or a synergistic effect when applied in combination with CDDP or ET, respectively. PENT potentiated the antitumor effect of ET in a nude-mouse xenograft model using PC-14 cells, when PENT was administered at 150 mg/kg subcutaneously for 6 days. Flow cytometry revealed that PENT decreased the accumulation of cells in the G2+M phase caused by CDDP when using PC-9 cells. However, PENT did not remarkably alter the accumulation of cells in G2+M caused by ET. These results suggest that PENT enhanced the antitumor effects of CDDP additively and those of ET synergistically. The enhancement mechanism probably differs between CDDP and ET. PENT needs more study to elucidate its potency as a new agent for combination chemotherapy.

High-dose pentoxifylline in patients with AIDS: inhibition of tumor necrosis factor production. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group.

Tumor necrosis factor-alpha (TNF) may activate human immunodeficiency virus (HIV), antagonize zidovudine activity, and contribute to AIDS wasting syndrome. Pentoxifylline decreases TNF production. In cell culture, pentoxifylline decreases HIV replication and gene expression. Since an AIDS Clinical Trial Group study suggested that pentoxifylline (400 mg thrice daily) is safe in AIDS patients and decreases TNF mRNA levels in peripheral blood mononuclear cells (PBMC), a second cohort received 800 mg thrice daily for 8 weeks. During treatment, the median decrease in TNF production by PBMC cultured with 0.1 microgram/mL lipopolysaccharide (LPS) was 40%. The median change in TNF mRNA was a 34% decrease. Pentoxifylline did not affect HIV levels as detected by quantitative microculture or serum p24 antigen measurements, nor did it alter zidovudine pharmacokinetics. The most common toxicity was gastrointestinal. Pentoxifylline at dosages of less than thrice-daily 800 mg is well tolerated and may decrease TNF mRNA levels and LPS-induced TNF production.

Differential responses of human sperm to varying concentrations of pentoxyfylline with demonstration of toxicity.

Pentoxyfylline (PF), a methylxanthine derivative, is an inhibitor of the cAMP-phosphodiesterase enzyme, and is known to stimulate the motility of fresh and post-thaw human sperm. The purpose of this study was to examine the effects of different concentrations of PF on motility (MOT), path (curvilinear) velocity (PV), and hyperactivation (HA) of fresh sperm from patients (n = 24) and donors (n = 6) and post-thaw donor sperm (n = 5). For cryopreservation, the donor semen was frozen in liquid nitrogen using test-yolk-glycerol cryopreservative, stored for a minimum of 48 hours, then thawed at room temperature prior to assay. Aliquots of all samples to equal 10 x 10(6)/ml were diluted in 1 ml of the following: medium (human tubal fluid) only (control), or 2.5, 5, 10, or 20 mg/ml PF in medium. Specimens were incubated at 37 degrees C, and all were assessed by computer-assisted motion analysis at 0, 0.5, 1, and 2 hours. The patient specimens were divided into two groups: group 1, mean percent (standard deviation [SD]) MOT < 20% (12.8 +/- 5.8); group 2, mean percent (SD) MOT > 20% (37.8 +/- 14). For fresh donor sperm, 2.5 mg/ml PF significantly stimulated PV and HA at 0, 1, and 2 hours, and MOT at 0, 0.5, and 2 hours. PF at 5 mg/ml resulted in a decreased PV and HA, whereas MOT was decreased by 10 mg/ml. In the < 20% MOT group, 2.5 mg/ml PF significantly stimulated MOT at 0.5, 1, and 2 hours, and HA at 0 and 2 hours. There was no effect on PV.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of pentoxifylline on the vascular toxicity secondary to cyclosporine in rats]. / Influence de la pentoxifylline sur la toxicité vasculaire secondaire à la cyclosporine chez le rat.

Chronic administration of cyclosporine (CyA) has been shown to affect local vascular tone. Pentoxifylline (PTX), a xanthine-derived vasoactive agent, has been reported to prevent CyA toxicity but its effect on CyA-related increased vascular tone remains uncertain. In vitro experiments were designed to study the effects of PTX on endothelium-dependent and independent vasorelaxation of the rat thoracic aorta. Three groups of rats (n = 10) were respectively treated for 4 weeks with CyA (30 mg/kg/day), CyA and PTX (40 mg/kg/day), and CyA and PTX (80 mg/kg/day). At the end of the period, rings (4-5 mm) of aorta were harvested and suspended in organ chambers containing Krebs Ringer solution (37 degrees C, 95% O2, 5% CO2) for assessment of endothelial and smooth muscle reactivity. Endothelium-dependent relaxation to acetylcholine was significantly enhanced in animals treated with CyA and PTX (40 mg/kg/day) compared to those exposed to CyA alone (p < 0.05). Response to histamine and adenosine diphosphate was not affected. However, the use of PTX (80 mg/kg/day) significantly deteriorated the endothelial response to the same drugs (p < 0.05) suggesting a detrimental effect of PTX at this concentration. Endothelial-independent relaxation to sodium nitroprusside was comparable in all groups. The results suggest the clinical benefit reported with the use of PTX on patients chronically exposed to CyA may partly be due to an improvement of the vascular endothelial function. However, the toxicity encountered at high dose should cautioned its use in clinical setup.

Effect of pentoxifylline on radiation damage and tumor growth.

PURPOSE: Inactivation of tumor cells by photon irradiation can be markedly improved by tumor oxygenation. We have investigated the effect of the vasoactive drug pentoxifylline with respect to cell toxicity, radiation sensitivity, repair and tumor growth. METHODS: V79 and Hela cell survival curves and determination of the tumor volume using rhabdomyosarcoma growth in BALB/c mice. RESULTS: In the presence of 1 mM pentoxifylline, survival of V79 Chinese hamster lung fibroblasts and human Hela cells at a dose level of 2 Gy is reduced by factors of 1.12 +/- 0.09 and 1.62 +/- 0.10 S.E. respectively. A radiosensitizing effect of pentoxifylline is also evident from the change of the alpha-coefficient which increases from 0.140 to 0.19 and from 0.39 to 0.65 in V79 and Hela cells respectively. In 3 h split dose experiments Hela cells but not V79 cells showed a change in the recovery ratio from 3.0 in control cells to 1.0 in drug exposed cells. In vivo experiments on BALB/c mice receiving 50 mg/kg pentoxifylline alone by subcutaneous injection showed a marked stimulation of tumor growth. When combined with irradiation we observed a 1.3 to 1.7 fold gain in tumor growth delay depending upon tumor size or day of measurement. CONCLUSIONS: The results suggest that pentoxifylline has an intrinsic effect on cell recovery and in tumors also improves blood supply and oxygenation.

Assessment of toxicity, clastogenicity, mutagenicity and transforming activity of pentoxifylline in mammalian cells cultured in vitro.

We tested the possible cytotoxic, clastogenic and genotoxic effects of pentoxifylline on different lines of mammalian cells cultured in vitro. This study was part of the developmental research of agapurin, since pentoxifylline represents an effective compound of this drug. Cells treated for a short time manifested a relatively high resistance to the toxic effects of pentoxifylline. Generally, only cells treated for a long time (18 h) or a short time (2 h) with high concentrations of drug manifested sensitivity to the toxic effects of pentoxifylline. Although the tested drug induced DNA synthesis inhibition in V79 and EUE cells and clastogenic effects in V79 cells, it was not able to induce either 6-TGr mutations in the HGPRT locus of V79 cells or morphological transformation of Syrian hamster embryo cells. Adding of microsomal fraction S9 to the treated cells did not markedly change the effects of pentoxifylline on different studied endpoints. We suggest that pentoxifylline has no genotoxic effects, and that the cytotoxicity and induction of chromosomal aberrations were induced by inhibition of cellular DNA replication.