Importance of nucleophilic thiols in modulating cyclophosphamide toxicity on the heart, urinary bladder and bone marrow of adult albino rats

ABSTRACT

Cyclophosphamide [CPH] is a synthetic antineoplastic agent, N-acetyl cysteine [NAC] and mesna [sodium 2 mercaptoethane sulphonate] are two members of the nucleophilic thiols. One hundred adult albino rats were used in this study. They were calssified into 10 equal groups. Groups I, II and III were control groups [-ve and +ve controls]. Group IV [Mesna alone]. The animals of this group received 4 doses of Mesna each of 25mg/kg I.P for 5 days as follows the 1[st] dose was given followed by the 2[nd] dose after 1/3 of an hour, then the 3[rd] dose was given after 3 hours followed by the 4[th] dose after another 3 hours. Group [V] [NAC alone] the animals of this group received NAC at a dose of 100 mg/kg orally for 5 days. Group [VI] [Mesna and NAC] the animals of this group received 4 doses of mesna and one dose of NAC concomitantly with the 2[nd] dose of mesna for 5 days following the same regimen and dose for each. Group [VII] [CPH alone] the animals of this group received cyclophosphamide in a dose of 50 mg/kg I.P for 5days. Group [VIII] [CPH and Mesna] the animals received 4 doses of mesna. CPH was given concomitantly with the 2[nd] dose of mesna. Both were given at the same previously mentioned doses and routes for 5 days. Group [IX] [CPH and NAC] the animals received CPH concomitantly with NAC at the same previously mentioned doses and routes for 5 days. Group [X] [CPH, mesna and NAC] the animals of this group received 4 doses of mesna. CPH and NAC were given concomitantly with the 2[nd] dose of mesna. All were given at the same previously mentioned doses and routes for each for 5 days. Animals of all groups were sacrificed 24 hours after the last dose. Blood samples were collected for investigating complete blood count [CBC], serum lactic dehydrogenase [LDH] and creatine phosphokinase [CPK] enzymes. Heart, urinary bladder and bone marrow were examined both histologically and histochemically. Cyclophosphamide significantly reduced the total leukocytic count [TLC], platelet count, hemoglobin concentration and lymphocytic count and increased the blood levels of LDH and CPK enzymes. Histologically CPH caused focal areas of cardiac necrosis, intramyocardial hemorrhage and Dilated, congested blood vessels. Whereas, it caused urinary bladder mucosal ulceration, interstitial edema and congestion with mononuclear cellular infiltration. Bone marrow hypocellularity, undifferentiated leukocytic series were also noticed in CPH group. Concomitant administration of mesna recovered completely the CPH-induced urinary bladder toxicity. However, it didn't improve either the blood picture or the cardiac enzymes and didn't recover completely neither the hemopoietic nor the cardiac toxicity of CPH. Whereas, concomitant administration of NAC or NAC and mesna with CPH improved completely the CPH induced hemopoietic and cardiac toxicity as indicated biochemically and histologically and to lesser extent the urinary bladder toxicity. So, it is recommended to prescribe NAC and mesna together with alkylating agents particularly cyclophosphamide to modulate its toxicity