Cardiovascular Toxicity Induced by Chronic Vincristine Treatment

Abstract

Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine’s better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 μg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.

De Novo transcriptome assembly and differential expression analysis of catharanthus roseus in response to salicylic acid

“…Vinblastine and vincristine are effective agents for treating various types of cancers, including leukemias, lymphomas, and other solid tumors 34 . To evaluate the effect of SA treatment on the production rate of these alkaloids, the amount of vinblastine and vincristine was measured at 1st, 2nd, 3rd and 7th days post-treatment by HPLC analysis (Fig.…”

Risk of cardiac-related death in astrocytoma patients treated with chemotherapy: A competing risk analysis using the SEER database

“…The main toxicities of procarbazine and lomustine (CCNU) are myelosuppression and gastrointestinal symptoms, while vincristine is neurotoxic and hepatotoxic, and has been reported to induce ischemic events due to its neurotoxicity ( 23 ). Additionally, chronic vincristine treatment may induce cardiovascular toxicity ( 5 ). TMZ is a type of oral alkylating agent with the most common side-effects being gastrointestinal and hematologic toxicity ( 24 ).…”

“…Antineoplastic therapy, such as chemotherapy, is known to prolong the survival of cancer patients. However, it can also induce cardiotoxicity, including cardiomyopathy, arrhythmias and other types of cardiovascular disease (CVD) (5,6). CVD has become the second leading cause of death in patients with CNS tumors (7)(8)(9).…”

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer

“…In addition, the vinca alkaloids vincristine and vinblastine, that block microtubule formation in mitotic spindle leading to the arrest of cell division of metaphase, may induce hypertension, angina, and ischemic heart disease [ 372 ]. Among the mechanisms proposed, Herradón and co-workers found that alterations of TNFα, eNOS and iNOS in cardiac tissue after chronic treatment with vincristine may be responsible for alterations of heart function; moreover, the increase in mitochondrial connexin 43 expression induced by vincristine suggests that this important cardioprotective regulator counteracts the detrimental increase in free radical to protect the heart tissue from apoptotic damage [ 372 , 373 ].…”