الفهرس 
AIM OF THE WORKOnly 14 pages are availabe for public view
 |  | from | 352 |  |  |
| | | from | 352 | | |
Abstract
SUMMARY A- The present work was designed to study the toxic effects from the use of anticancer drug (gleevec) during pregnancy and also the effects of this drug on the resulting fetuses from several points; (morphological, teratological, hematological, certain biochemical parameters, histological features of the liver and kidney and molecular studies).
B- Total number of forty adult female Sprague Dawley rats weighing from 150 to 170 gm. and twenty male rats 150 gm. each of the same strain were used. All Pregnant rats were divided into three main groups. The first group(8 rats) served as control. The second main group was divided into two subgroups(8 rats/each) and orally administered low dose of gleevec (36 mg/kg body weight ) dissolved in distilled water from 6th to 13th and from 13th to 19thday of gestation respectively. The third main group of pregnant rats was divided into two subgroups(8 rats/each) and orally administered high dose of gleevec dissolved in distilled water 54 mg/kg b.wt. from day 6 to day 13 of gestation and from 13th to 19th day of gestation respectively. The drug doses (36mg/kg and 54mg/kg ) related to the low and high human therapeutic doses
C- The results showed the following defects for gleevec treatment: 1-Gleevec caused reduction of maternal body weights, uterine and placental weights in the treated groups compared with the control group. Also, the high dose of gleevec (54 mg/kg b. wt. ) showed an increase in the percentage of abortion, partial and complete resorptions. 2-The drug also caused a growth retardation to the fetuses indicated by reduction of body weight and body length. 3- Fetuses of the mothers treated with the low dose of gleevec showed hemorrhage, red patches (hematoma)in all different parts of the body, contraction in the fore limbs and paralysis in hind limbs. In addition to these defects, the presence of exencephalic, encephalocoele, distended abdominal wall with internal hemorrhage and harelip with congenital cleft or fissure in the midline of the upper lip were observed in the fetuses of the mothers treated with the high dose of gleevec 4-Both doses of gleevec caused a marked increase of prenatal loss. 5-Skeletal preparations of fetuses maternally treated with Gleevec showed growth retardation and incomplete ossification of some skeletal elements such as, skull bones, vertebral columnsternum, ribs, vertebrae, pectoral girdle, fore limb bones, pelvic girdle and hind limb bones. 6-Biochemical studies of pregnant rats: a- The administration of gleevec at 36 and 54 mg/kg b. wt. to pregnant rats from 6th-13th and from 13th -19th day of gestation induced a marked decrease of hemoglobin content, red blood corpuscles, white blood cells and blood platelets counts compared to their respective control. No significant difference (p>0.05) in white blood cells count was found between control group and rats treated with the low dose of gleevec (36 mg/kg) from 6th -13th day of gestation and from day 13 to day 19 of gestation. b-Alanin aminotransferase (ALT),Aspartate aminotrans- ferase (AST) liver enzymes values, total bilirubin levels, direct bilirubin, alkaline phosphatase were increased at the two doses of gleevec from day 6 to day 13 and from day 13 to day 19 of gestation, while serum albumin, total protein were decreased as compared to their respective control. c- Treatment with the high dose 54mg/kg of gleevec from day 6 to day 13 and from day 13 to day 19 of pregnancy caused marked elevation in the blood urea and serum creatinine levels as compared with control group. The sera levels of urea in the group
of rats administered 36 mg/kg gleevec from day 6 to day 13 of gestation showed non-significant increase as compared with control group, whereas pregnant rats administered the same dose of gleevec from day 13 to day 19 of gestation exhibited a marked elevation in the level blood urea as compared to the normal control group. On the other hand, no significant difference was detected in serum creatinine levels of pregnant rats administered low dose of gleevec 36 mg/kg of both subgroups as compared to the normal control group. 7-Histological pattern of organs:
a) Histological examination of the livers of treated mothers and their fetuses of the both treated groups revealed different phases of histopathological changes. These changes were represented by marked congestion of blood vessels and sinusoids, cloudy swelling, hydropic degeneration, vacuolar degeneration, necrosis of hepatic cells and loss of hepatic architecture.
b) The kidney of pregnant rats and their fetuses showed cell damage like degenerative changes such as cloudy swelling and hydropic degeneration, swollen and destruction of the proximal and distal convoluted tubules, shrinkage and bilobed glomerular tufts, crescent shaped urinary space of
some glomeruli. Glomerulonephritis along with renal nuclear pyknosis and karyorrhexis were the most prominent histological changes observed in the kidney of both pregnant rats and their fetuses after gleevec treatment. Also, a large focal area of fibrosis was noticed in between the kidney tissue treated with the high dose of gleevec. The tissues of pregnant rats and their fetuses have been seriously affected as a response to the toxic impacts of the applied doses of Imatinib. Nonetheless, the magnitude of these pathological impairments has been noticed to be dose dependent indicating that such impairments were more conspicuous in the high dose of Imatinib (54 mg /kg b. wt. gleevec) from 6th -13th and from 13th -19th day of gestation than the smaller one treated with 36 mg /kg b. wt.8-Molecular studies (Liver DNA fragmentation): Agarose gel electrophoresis of the liver genomic DNA for pregnant mothers (treated with gleevec at doses of 36 &54 mg/kg b.wt. from 6th -13th and from 13th -19th day of gestation) and their fetuses revealed DNA damage in the form of smearing as well as ladder like fragmentation. DNA fragmentation of the pregnant rats was elevated and more affected with the toxicity of gleevec than the fetuses