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Biomedical subjects

E Verbeken

Publications and source records attributed to E Verbeken.

At least 37 records · Page 2Linked to original sources
PubMed2001

Optimal dosing of intravascular low-power red laser light as an adjunct to coronary stent implantation: insights from a porcine coronary stent model.

BACKGROUND: It is believed that restenosis following coronary interventions is the result of endothelial denudation that leads to thrombus formation, vascular remodeling, and smooth muscle cell proliferation. Low-power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo, and reduces restenosis in animal models. The present study investigated the optimal dose of intravascular LPRLL therapy in the prevention of in-stent stenosis in a porcine coronary stent model. METHODS AND RESULTS: Selected right coronary artery segments were pretreated with a LPRLL balloon, delivering a dose of 0 mW during 1 min (group 1, n = 10), 50 mW during 1 min (group II, n = 10), or 100 mW during 1 min (group III, n = 10) before stenting. Quantitative coronary analysis of the stented vessel was performed before stenting, immediately after stenting, and at 6 weeks follow-up. The pigs were sacrificed, and histologic and morphometric analyses were conducted. At 6 weeks, minimal luminal stent diameter was significantly narrower in the control group compared to the 50-mW dose group (p < 0.05). These results were confirmed by morphometric analysis. Neointimal area was also significantly decreased in the 50-mW dose group. CONCLUSIONS: Intravascular LPRLL contributes to reduction of angiographic in-stent restenosis and neointimal hyperplasia in this animal model. The optimal dose using the LPRLL balloon system seems to be approximately 5 mW delivered during 1 min.

Animals↗
PubMed2001

Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease.

The epithelial polymeric immunoglobulin receptor/transmembrane secretory component (pIgR/SC) transports into secretions polymeric immunoglobulin A (pIgA), which is considered the first line of defense of the respiratory tract. The present study, done with quantitative immunohistochemistry, evaluated epithelial expression of secretory component (SC) and Clara cell protein (CC16) and neutrophil infiltration into the airways of eight patients with severe chronic obstructive pulmonary disease (COPD) who were undergoing lung transplantation, as compared with these processes in six nonsmoking patients with pulmonary hypertension who were used as controls and in lung specimens from five smokers without chronic bronchitis. Staining for SC was significantly decreased in the COPD patients as compared with the controls, both in large (mean optical density [MOD]: 23.4 [range: 21.1 to 27.8] versus 42.2 [range: 28.2 to 49.3], p = 0.003) and in small airways (MOD: 30.8 [range: 20.3 to 39.4] versus 41.5 [range: 39.2 to 46.2], p = 0.003). SC expression in small airways correlated strongly with functional parameters such as FEV1 (Kendall's tau (K) = 0.76, p = 0.008), FVC (K = 0.64, p = 0.03), and midexpiratory flow at 50% of VC (MEF50) (K = 0.74, p = 0.01). The reduced expression of SC in large airways correlated with neutrophil infiltration in submucosal glands (K = -0.47, p = 0.03). Expression of CC16 in the bronchial epithelium of COPD patients was also significantly decreased as compared with that of controls, especially in small airways (MOD: 28.3 [range: 26.8 to 32.4] versus 45.8 [range: 40.7 to 56.0], p = 0.002), but no correlation was observed with lung function tests. In conclusion, this study shows that reduced expression of SC in airway epithelium is associated with airflow obstruction and neutrophil infiltration in severe COPD.

Adolescent↗
PubMed2001

Antimineralization treatments in stentless porcine bioprostheses: an experimental study.

BACKGROUND AND AIM OF THE STUDY: Photo-oxidation treatment of porcine stentless bioprostheses (Photofix) was compared with glutaraldehyde fixation, with either AOA (Freestyle valve) or Tween-80 (Edwards Prima Plus valve). METHODS: Six valves of each type were implanted in juvenile sheep, in the pulmonary position. Valves were explanted after three or six months and examined macroscopically, by X-radiography, and by light and transmission electron microscopy. Calcium content was determined by atomic absorption spectrometry. RESULTS: The cusps of all valves were free of calcification, and had normal histology and function. Calcium contents (median +/- IQR) were 0.63+/-0.45, 0.73+/-1.46 and 0.46+/-1.42 microg/mg for the Photofix, Freestyle and Prima Plus valves, respectively (p = NS). Calcium contents of the aortic wall portions were 0.71+/-1.27 (Photofix), 10.78+/-77.22 (Freestyle) and 28.70+/-66.53 (Prima Plus) (p <0.05 for Photofix versus Freestyle or Prima Plus). CONCLUSION: Photo-oxidation of a porcine stentless valve prevents calcification not only in the cusps, but also in the aortic wall portion.

Animals↗
PubMed2001

Influence of species, environmental factors, and tissue cellularity on calcification of porcine aortic wall tissue.

Valve tissue calcification has complex host, implant, and mechanical determinants. We studied the influence of species (rat v sheep), environmental factors (presence v absence of blood contact and arterial stress), and tissue cellularity (normal v acellularized tissue) on porcine aortic wall mineralization. Porcine aortic wall samples underwent standard glutaraldehyde-fixation or combined enzyme-detergent acellularization. Samples were implanted subcutaneously in rats (n = 8) and in juvenile sheep (n = 8). Furthermore, in juvenile sheep, similar samples were implanted into the jugular vein (blood contact) and into the carotid artery (blood contact and arterial stress). After 8 and 12 weeks, tissue was explanted and evaluated by X-ray, light- and electron-microscopy, and calcium content measurement (atomic absorption spectrometry). On the Von Kossa staining, auto-fluorescence of elastic fibers was used to identify the relation between calcific deposits and elastin. Subcutaneously implanted, glutaraldehyde-fixed tissue calcified severely in rat, but much less in sheep (calcium content: 56.2 +/- 13.6 v 9.9 +/- 9.0 microg/mg, respectively; P <.001). In sheep, the presence of blood contact (venous implants) increased wall calcification significantly (36.9 +/- 15.8; P <.001), but hemodynamic stress (arterial implants) had no additional mineralizing effect on the aortic wall (P >.05 v venous implants). Calcification of glutaraldehyde-fixed tissue occurred predominantly at the level of cells and cellular remnants, as confirmed by electron- and fluorescence-microscopy, locating calcific deposits in between elastic fibers. Acellularized tissue calcified significantly less, but an inflammatory response towards the tissue led to fragmentation, lysis, and subsequent calcification of elastic fibers. Results from subcutaneous implantations show large inconsistencies in calcification between the species. In sheep, blood contact increases aortic wall calcification significantly, while arterial stress has no additional effect. The sheep-jugular implantation model can be used as a simplified model for further study of aortic wall calcification and new antimineralization treatments. Calcification of glutaraldehyde-fixed aortic wall tissue is initiated at the level of cellular remnants, with little or no contribution from elastic fibers. Acellularization can avoid this cell-mediated calcification, but an additional treatment (glutaraldehyde, cryopreservation, photo-fixation,.) will be necessary to avoid the inflammation leading to elastolysis and consequent calcification of elastic fibers.

Animals↗
PubMed2000

Intravascular low-power red laser light as an adjunct to coronary stent implantation: initial clinical experience.

Low-power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo and reduces restenosis in animal models. The present study reports the preliminary clinical experience in our center. Eighty-one patients were treated with LPRLL, 30 mW/1 min, for in-stent restenosis (n = 27), elective stenting for recurrent restenosis (n = 16), and stenting for treatment of a suboptimal PTCA result (n = 38). All interventions were successful and no major adverse events due to LPRLL therapy were observed. At follow-up, 12 patients (14.8%) underwent an early control coronarogram due to target vessel restenosis. At 6 months, another 20 patients showed a significant restenosis of the target vessel. Preliminary clinical evaluation demonstrates that LPRLL is feasible and safe. The preliminary results suggest that LPRLL results in a decrease of in-stent restenosis when used during primary stenting.

Angioplasty, Balloon, Coronary↗
PubMed2000

Effect of transmyocardial laser revascularization on chronic ischemic hearts in sheep.

BACKGROUND: We investigated the effect of transmyocardial laser revascularization (TMR) on myocardial function and regional blood flow in an animal model of ischemic heart disease. METHODS: Chronic ischemia was induced in 11 sheep by the application of coronary stenosis on the left anterior descending (LAD) and circumflex coronary artery (LCX). Ten weeks later, in six of them, transmyocardial channels were created in the anterior free wall and in the posterior wall of the left ventricle. Five animals served as controls. The myocardial function was assessed by echocardiography taken at baseline and every 2 weeks after coronary stenosis and after TMR. Myocardial perfusion was measured by colored microspheres, injected at baseline, immediately after coronary stenosis, before and after TMR, and at 20 weeks after coronary stenosis. The hearts were retrieved at 20 weeks for light microscopic examination. RESULTS: The left ventricular end-diastolic and end-systolic cavity area was elevated 20 weeks after coronary stenosis in the control and TMR groups. There was no difference between groups (analysis of variance; ANOVA, non-significant). The wall thickening fraction (WTF) decreased progressively and significantly after coronary stenosis in both groups. The WTF was further acutely reduced by TMR, and recovered gradually to the pre-TMR level. No significant difference in WTF was observed between the TMR and control groups. The resting myocardial blood flow was significantly increased by TMR at 20 weeks (P=0.03). Light microscopic examination revealed channel patency in 49% of the laser scars at 10 weeks post-TMR. A dense capillary network was observed at the edges of the surrounding scar. CONCLUSIONS: In an experimental model of ischemic heart disease, TMR developed angiogenesis in the lased channels, but, however, failed to improve myocardial function.

Animals↗
PubMed2000

Lung development following diaphragmatic hernia in the fetal rabbit.

Diaphragmatic hernia was created in 39 rabbit fetuses on day 23 of gestation. Fifteen fetuses underwent a sham thoracotomy (SHAM). Thirty-nine non-operated littermates served as internal controls (CTR). Fetuses were harvested by Caesarean section on days 25, 27, 29 and 30 of gestation. Pulmonary response was evaluated by lung to body weight ratio (LBWR), morphometry, and density of type II pneumocytes. No difference was found between CTR and SHAM fetuses at term. CDH fetuses had smaller lungs (LBWR 0.014 +/- 0.004 versus 0.030 +/- 0.04 in CTR, P < 0.0001), a less complex acinus [mean terminal bronchial density (MTBD) 1.786 +/- 0.408 versus 0.917 +/- 0. 188, P < 0.0001], thicker alveolar septa [mean wall transection length (LMW) 0.0221 +/- 0.008 versus 0.0142 +/- 0.002, P = 0.0003], and a lower type II cell count (144.5 +/- 19.33 versus 216.2 +/- 27.85 per high power field, P < 0.0001). The differences in MTBD and LMW were significant from gestational day 25 onwards, and the differences in type II cell count from day 27 onwards. Surgical diaphragmatic hernia in rabbit fetuses in the late pseudoglandular phase reproduces many features of the pulmonary hypoplasia associated with human congenital diaphragmatic hernia, including the delayed maturation. The effects are present within 2 days following experimental diaphragmatic hernia and progress over time.

Animals↗
PubMed2000

The influence of stenting on the behavior of amino-oleic acid-treated, glutaraldehyde-fixed porcine aortic valves in a sheep model.

BACKGROUND AND AIM OF THE STUDY: The durability of freehand-sewn aortic valve homografts used for valve replacement in humans is greater than for stented aortic homografts. In analogy with this, it is expected that the durability of a stentless heterograft will be superior to that of its stented counterpart. Our objective was to investigate the influence of stenting on amino-oleic acid (AOA)-treated, glutaraldehyde-fixed porcine aortic valve bioprostheses. METHODS: Twelve young sheep underwent implantation of porcine aortic valves in the pulmonary artery: six porcine aortic stentless valves (Freestyle) and six porcine aortic stented valves (Mosaic). In each series, three valves were explanted after three months, and three after six months. Valves were analyzed by gross inspection, radiography, histology, and transmission electron microscopy. Quantitative determination of calcium content was made with atomic absorption spectrometry. RESULTS: The porcine aortic stentless valve showed extensive calcification of its aortic wall portion, but had perfectly functioning, pliable cusps without calcification up to six months. The cusps of porcine aortic stented valves were also pliable and functioning without calcification up to six months. Only minimal calcification was seen in the aortic wall of the stented valves. At six months after implantation the cusps of stentless valves contained significantly less calcium than those of stented valves (2.7+/-1.2 microg/mg and 7.9+/-2.3 microg/mg, respectively; p = 0.011). However, the aortic wall from stentless valves contained significantly more calcium than that of stented valves (three-month explants: 39.2+/-14.4 versus 7.2+/-2.8 microg/mg; p <0.05; six-month explants: 49.3+/-14.0 versus 14.1+/-5.9 microg/mg; p <0.05). CONCLUSION: These data suggest that stenting does influence cuspal calcification of AOA-treated, glutaraldehyde-fixed porcine aortic valves.

Amino Acids↗
PubMed2000

Evaluation of the biocompatibility of two new diamond-like stent coatings (Dylyn) in a porcine coronary stent model.

UNLABELLED: Hydrogenated diamond-like carbon films (DLC, a-C:H), deposited using plasma-assisted or ion beam-assisted techniques, offer great potential as self-lubricating coatings in many tribological applications. Additionally, studies on biocompatibility have shown that DLC is an inert, impervious hydrocarbon with properties suitable for use in the biomedical field. One particular class of modified DLC coatings are diamond-like nanocomposite coatings (DLN or Dylyn , Bekaert, Kortrijk, Belgium), which offer promising solutions for many industrial applications. In this study, the biocompatibility of two diamond-like stent coatings are evaluated in a porcine coronary stent model. METHODS: Either coated or non-coated stents were randomly implanted in two coronary arteries of 20 pigs so that each group contained 13 stented arteries. Pigs underwent a control angiogram at 6 weeks and were then sacrificed. Quantitative coronary analysis before, immediately after stent implantation, and at 6 weeks was performed using the semi-automated Polytron 1000 system (Siemens, Erlangen, Germany). Morphometry was performed using a computerized morphometric program. Angiographic analysis showed similar baseline selected arteries and post-stenting diameters. At 6-week follow-up, there was no significant difference in minimal stent diameter. Histopathology revealed a similar injury score in the 3 groups. Inflammation was significantly increased in the DLN-DLC coating group. Thrombus formation was significantly decreased in both coated stent groups. Neointimal hyperplasia was decreased in both coated stent groups; however, the difference with the non-coated stents was not statistically significant. Area stenosis was lower in the DLN-coated stent group than in the control group (41 +/- 17% vs. 54 +/- 15%; p = 0.06). CONCLUSION: The results indicate that the diamond-like nanocomposite stent coatings are compatible, resulting in decreased thrombogenicity and decreased neointimal hyperplasia. Covering this coating with another diamond-like carbon film (DLC) resulted in an increased inflammatory reaction and no additional advantage compared to the single-layer diamond-like nanocomposite coating.

Animals↗
PubMed2000

Dynein arms and spokes after ciliogenesis in cultured respiratory epithelial cells from non-PCD individuals.

Dynein arms and spokes are crucial components of cilia. Reference values for the dynein arms and spokes were calculated based on biopsies from non-PCD patients as well as after ciliogenesis in culture. The mean values in the biopsies (n = 251) were 8.4 +/- 0.5, 2.9 +/- 0.7 and 4.7 +/- 1.0 for the outer dynein arms, inner dynein arms and spokes respectively. After ciliogenesis in culture (n = 462) identical values were found: 8.7 +/- 0.4, 3.0 +/- 0.4 and 5.5 +/- 0.6. The lower limits of normality can be set at 7.0 and 1.2 for the outer and inner dynein arms respectively. The dynein arms and spokes were not influenced by the percentage of secondary abnormalities. In conclusion, dynein arms and spokes are readily identified after ciliogenesis in culture. These parameters are independent of secondary ciliary dyskinesia.

Biopsy↗
PubMed2000

Secondary ciliary dyskinesia is absent after ciliogenesis in culture.

Ultrastructural secondary ciliary dyskinesia (SCD) was measured using transmission electron microscopy in 301 biopsies and 439 samples after ciliogenesis in the sequential monolayer-suspension culture. Biopsies were taken in the context of exclusion of primary ciliary dyskinesia. SCD was frequently found in the biopsies: only 30% of the samples were normal (SCD < 5%), the mean percentage of SCD abnormalities was 11.9 +/- 12.9%. In 1/8 of the samples severe SCD (> 25%) was present. The most frequently encountered SCD abnormality was the membrane bleb, followed by the various peripheral microtubular abnormalities. With increasing total SCD the absence of the central pair became more important. After ciliogenesis in culture SCD was virtually absent: 1.0 +/- 1.8% for all 439 samples, 96% of the samples were within limits of normality (SCD < 5%). Moderate (15-25%) and severe SCD (> 25%) were never found. In more than 50% of the samples not one abnormality was found. There was no relation between the SCD in the biopsy and that after ciliogenesis. The absence of SCD after ciliogenesis is a major advantage for the diagnosis of PCD, specifically in cases with central pair abnormalities, peripheral microtubular pair abnormalities and those without a primary ultrastructural abnormality.

Biopsy↗
PubMed2000

Ultrastructural expression of primary ciliary dyskinesia after ciliogenesis in culture.

During the period 1990-1999 84 PCD patients were identified and characterized. The expression of inherited abnormalities in primary ciliary dyskinesia after ciliogenesis was investigated in 41 patients with dynein deficiency, 6 patients with absence of the central pair of microtubules and 24 PCD patients with normal ultrastructure. In patients with dynein deficiency, the outer dynein arms counts were 1.9 +/- 1.0 in the biopsies and 1.6 +/- 0.7 after ciliogenesis. Secondary abnormalities were found in 15.8 +/- 20.4% of the transverse sections of cilia and only in 1.0 +/- 1.3% after ciliogenesis. Ciliary orientation was 28 +/- 11 degrees and 24 +/- 10 degrees respectively in biopsies and cultures. In patients with absence of the central pair this was found in 15 +/- 16% in biopsies and 21 +/- 19% after ciliogenesis. The values for the outer dynein arm were 8.4 +/- 0.3 and 8.7 +/- 0.2 and for the secondary abnormalities were 11.7 +/- 7.3% and 0.5 +/- 1.3% in the biopsies, respectively after ciliogenesis. In patients with normal ultrastructure the scores for the dynein arms were similar. Secondary abnormalities were found in 12.2 +/- 11.7% in the biopsies and 0.6 +/- 0.9% after ciliogenesis while ciliary orientation was respectively 21 +/- 7 degrees and 25 +/- 8 degrees. In conclusion, inherited abnormalities in primary ciliary dyskinesia are expressed after ciliogenesis, while secondary abnormalities are virtually absent, thereby facilitating the ultrastructural diagnosis.

Biopsy↗
PubMed1999

A novel animal model for hemangiomas: inhibition of hemangioma development by the angiogenesis inhibitor TNP-470.

Hemangiomas represent the most frequent tumors of infancy. However, the pathogenesis of these tumors is still largely unknown, and current treatment of juvenile hemangiomas remains unsatisfactory. Here we present a novel animal model to study proliferating hemangiomas and to evaluate the effect of angiostatic compounds on their growth. Intraperitoneal (i.p.) infection of 4-day-old rats with murine polyomavirus resulted in the development of multiple cutaneous, intramuscular (i.m.), and cerebral hemangiomas with 100% frequency. Histological examination of the brain revealed the formation of immature lesions as soon as 4 days postinfection (p.i.). The subsequent exponential growth of the hemangiomas, both in number and size, was associated with severe hemorrhage and anemia. The cerebral, cutaneous, and i.m. lesions consisted of blood-filled cysts, histologically similar to human cavernous hemangiomas and stained positive for proliferating cell nuclear antigen, urokinase-type plasminogen activator, and vascular endothelial growth factor. Mature cerebral hemangiomas also expressed von Willebrand factor. Cerebral lesions caused death of the untreated animals within 19.2 +/- 1.1 days p.i. Remarkably fewer and smaller hemangiomas developed in animals that had been treated s.c. with the angiogenesis inhibitor TNP-470. Accordingly, TNP-470 (50 mg/kg), administered twice a week from 3 days p.i., significantly delayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3 (P < 0.001)]. Even if therapy was initiated when cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.), a significant delay in hemangioma-associated mortality was observed. Also, the IFN-inducer polyinosinic-polycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated mortality when administered i.p. at 5 mg/kg, twice a week, starting at day 3 p.i. The model described here may be useful for investigating (a) the angiogenic mechanism(s) underlying hemangioma progression; and (b) the effect of anti-angiogenic compounds on vascular tumor growth.

Animals↗
PubMed1999

Calcification characteristics of porcine stentless valves in juvenile sheep.

OBJECTIVE: To compare calcification characteristics of two porcine stentless valves (Toronto SPV and Freestyle) with different designs, fixation and antimineralization techniques using a juvenile sheep model of valve implantation inside the circulation. METHODS: The stentless valves (n = 2 x 6) were implanted in juvenile sheep in the pulmonary artery as an interposition, while the circulation was maintained with a right ventricular assist device. The model was validated by the implantation of, clinically well-known, porcine (Hancock II) and pericardial (Pericarbon) valves. Half of the valves were explanted after 3 months, the rest after 6 months. Valves were examined macroscopically, by X-ray, light microscopy (HE, Masson, Von Giesson, Von Kossa, PTAH stains), and transmission electron microscopy. Quantitative determination of the calcium content of the cusps was performed with atomic absorption spectrometry. RESULTS: After 3 months, the Freestyle had an extensively calcified aortic wall, most prominent at the outflow side of the porcine valve. After 6 months, calcification increased transmurally, but the valve cusps were free of calcification, and the inflow side was only slightly calcified. The Toronto SPV valve also started to calcify at the inflow side of the valve after 3 months with increased calcification after 6 months. The base of the Toronto SPV valve cusps showed slight calcification after 6 months of implantation. CONCLUSIONS: The pattern of calcification of the porcine aortic wall differs between the two studied stentless valves, with calcification located predominantly at the outflow side in the Freestyle valve, but also at the inflow side in the Toronto SPV valve. The cusps of the Freestyle valve were less prone to calcification than those from the Toronto SPV valve.

Animals↗
PubMed1999

Medical thoracoscopic lung biopsy in interstitial lung disease: a prospective study of biopsy quality.

The aim of this study was to analyse the quality and diagnostic value of lung biopsies for the diagnosis of interstitial lung disease (ILD), taken with diathermy coagulation cup forceps during medical thoracoscopy. Patients with ILD, not specified after thorough clinical assessment, high-resolution CT (HRCT), bronchoalveolar lavage and transbronchial biopsy, were studied. Medical thoracoscopy was performed in an endoscopy suite under neuroleptic anaesthesia with spontaneous ventilation. Biopsy specimens were analysed prospectively by one lung pathologist blinded to the clinical findings. Over 2 yrs, 118 samples were analysed from 24 consecutive patients. A good quality biopsy was obtained in 23 patients, and 78% of the samples were of good quality. Biopsy findings plus clinical and HRCT data revealed a relevant diagnosis in 18 patients and some diagnostic clues in four patients, for whom further examinations were needed. No major complications occurred. Chest tube drainage averaged 5.3+/-4.7 days, and was related to the total lung capacity (p=0.008), which mirrors the severity of ILD. Separate sampling of biopsies from different lobes proved to be useful in one third of the cases. In conclusion, lung biopsy sampling can be performed safely by interventional pulmonary endoscopists and has a good diagnostic yield in interstitial lung disease of unknown origin.

Adult↗
PubMed1999

Mucormycosis, a threatening opportunistic mycotic infection.

Mucormycosis is a rare and invasive mycotic opportunistic infection, occurring mostly in predisposed patients, mainly diabetics and immunocompromised individuals. The evolution of this fungal infection is frequently fatal unless aggressive treatment is started, or predisposing factors are handled. Our first patient was a known diabetic who had ketoacidotic coma at admission, complicated with pulmonary mucormycosis, and needed surgical resection followed by antimycotic therapy. The second patient did not survive his severe aplastic anemia (with neutropenia) and hemochromatosis (treated with desferrioxamine), complicated with a systemic Rhizopus infection, despite treatment with amphotericin B and granulocyte-colony-stimulating factors.

Acute Kidney Injury↗
PubMed1999

9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine: a novel prodrug of 9-(2-phosphonylmethoxyethyl)guanine with improved antitumor efficacy and selectivity in choriocarcinoma-bearing rats.

The novel acyclic nucleoside phosphonate analogue 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPr-PMEDAP) was shown in vitro to act as an intracellular prodrug of 9-(2-phosphonylmethoxyethyl)guanine (PMEG). We compared the in vivo antitumor efficacy and selectivity of cPr-PMEDAP, its progenitor PMEDAP, and PMEG in a rat choriocarcinoma tumor model. The rats, inoculated with rat choriocarcinoma (RCHO) cells under the renal capsule, were treated IP during 10 days. Macroscopical and histological examination of the RCHO-inoculated kidneys was performed at two time points (i.e., immediately after the end of treatment or after an additional drug-free period of 2 weeks). Complete inhibition of choriocarcinoma tumor development was achieved upon treatment with cPr-PMEDAP, PMEG, and PMEDAP at a daily dose of 10, 1, and 50 mg/kg, respectively. At these doses, all three compounds produced moderate to strong toxicity (evidenced by atrophy of lymphoid organs and reduced body weight gain). When compared at the maximum tolerated (sublethal) doses (i.e., 0.5, 10, and 50 mg/kg for PMEG, cPr-PMEDAP, and PMEDAP, respectively), cPr-PMEDAP proved superior to PMEG and PMEDAP in achieving a complete inhibition of tumor development. Also, whereas PMEG was unable to produce a prolonged antitumor effect, the animals treated with cPr-PMEDAP still showed prominent inhibition of tumor development when tumor size was evaluated at 2 weeks after end of treatment. Based on its efficacy and therapeutic safety, cPr-PMEDAP can be regarded as a promising antitumor agent, which merits further in vivo evaluation in additional tumor models for human neoplasms.

Adenine↗