Cardiovascular safety profile of taxanes and vinca alkaloids: 30 years FDA registry experience

ObjectiveAntimicrotubular agents are among the most commonly used classes of chemotherapeutic agents, but the risk of cardiovascular adverse events (CVAEs) remains unclear. Our objective was to study the CVAEs associated with antimicrotubular agents.MethodsThe Food and Drug Administration’s Adverse Event Reporting System was used to study CVAEs in adults from 1990 to 2020. Reported single-agent (only taxane or vinca alkaloid) CVAEs were compared with combination therapy (with at least one of the four major cardiotoxic drugs: anthracycline, HER2Neu inhibitors, tyrosine kinase inhibitors and checkpoint inhibitors) using adjusted polytomous logistic regression.ResultsOver 30 years, 134 398 adverse events were reported, of which 18 426 (13.4%) were CVAEs, with 74.1% due to taxanes and 25.9% due to vinca alkaloids. In 30 years, there has been a reduction in the proportion of reported CVAEs for taxanes from 15% to 11.8% (Cochran-Armitage P-trends <0.001) with no significant change in the proportion of reported CVAEs for vinca alkaloids (9.2%–11.7%; P-trends=0.06). The proportion of reported CVAEs was lower in both taxane and vinca alkaloid monotherapy versus combination therapy (reporting OR=0.50 and 0.55, respectively). Anthracyclines and HER2Neu inhibitor combinations with taxanes or vinca alkaloids primarily drove the higher burden of combination CVAEs. Hypertension requiring hospitalisation and heart failure was significantly lower in monotherapy versus combination antimicrotubular agent therapy.ConclusionsAntimicrotubular agents are associated with CVAEs, especially in combination chemotherapy regimens. Based on this study, we suggest routine cardiovascular assessment of patients with cancer before initiating antimicrotubular agents in combination therapy.

Combrestatin derivatives as microtubular assembly inhibitors at colchicine binding site

: Colchicine binding site in microtubules is among the most flourishing target for anticancer remedy. Microtubule inhibitor drugs, including combrestatin phosphate, paclitaxel and Vinca alkaloids, were formerly considered to exert their activity primarily by increasing or decreasing the cellular microtubule mass. This review describes the microtubular assembly along with the combrestatin derivatives as microtubules inhibitors, the structures of compounds known to interact with colchicines binding site, and their possible mechanism of action. Additionally, we have also discussed the utility of other heterocyclic rings and their combrestatin derivatives in treating cancer. Colchicines binding site represents a stimulating new molecular target in the design of combrestatin drugs.

Cardiotoxic Effects of Yew Tree and Pink Periwinkle Alkaloids

Antitumour herbal medicines based on pink periwinkle and yew tree alkaloids are included in combination therapies for many types of cancer. The use of these classes of products may entail cardiotoxic effects leading to life-threatening conditions. The aim of the study was to analyse scientific literature on cardiotoxic effects of anticancer drugs based on yew tree alkaloids (taxanes) and pink periwinkle alkaloids (vinca alkaloids). The results of the analysis demonstrated that the main manifestations of taxane-induced cardiotoxicity were bradycardia, atrioventricular block, atrial and ventricular arrhythmias. Concomitant use of taxanes and anthracycline antibiotics exacerbated cardiotoxic effects of both drug classes. The use of vinca alkaloids was associated with haematological toxicity in the form of neutropenia, while cardiotoxic effect was rarely observed during monotherapy. Raising awareness among oncologists, cardiologists, and other specialists involved in the management of cancer patients about potential cardiac complications of antitumour therapy contributes to early detection of adverse reactions and allows for individual correction of treatment regimens, especially in patients with predisposition to cardiovascular disease.

Predictive Assay for Chemotherapy-Induced Peripheral Neuropathy Associated with Vinca Alkaloids in Lymphoid Malignancies

Introduction: Vinca alkaloids, such as vincristine, are important anticancer agents mainly employed in the treatment of hematological cancers. The principal mechanism for the antineoplastic activity is microtubule disruption. However, these agents also cause damage to mitochondria which leads to oxidative stress and production of reactive oxygen species (ROS). Other chemotherapeutic drugs that are suggested to cause peripheral neuropathy by this mechanism, i.e., increased oxidative stress, include taxanes and platinum compounds. Oxidative damage to peripheral neurons can cause damage to myelin sheath, mitochondrial proteins, and other antioxidant enzymes, resulting in hyperexcitability of peripheral neurons. This nerve damage results in the commonly seen dose-limiting neurological side effect chemotherapy-induced peripheral neuropathy (CIPN). Hence, assessment of biomarkers for peroxidation, myelin repair/maintenance, and red-ox balance (glutathione recycling) can be helpful in monitoring the on-set and course of peripheral neuropathy. We hypothesize that chemotherapeutic agents with similar effects on mitochondria (vinca alkaloids, taxanes and platinum compounds) will produce a specific pattern of glutathione recycling in patients prone to CIPN. Methods: Patients who had given written consent to participate in this exploratory single-centered, prospective IRB approved study contributed a blood sample prior to each treatment cycle. At each visit, the Rotterdam Symptoms Check-List (RSCL) was filled out and reported symptoms confirmed by comparison to notes in medical records. Whole blood was analyzed for glutathione recycling capacity using the bioactive probe hydroxyethyldisulfide (HEDS) and incubated at room temperature for 2 hours with gentle mixing. Prior to spectrophotometric determination, blood cells and proteinaceous thiols will be removed from the sample by acid precipitation and centrifugation. The final spectrophotometric reading will be converted into ME produced using the conversion factor provided in the assay kit Rockland Inc). Recycling capacity was compared to self-reported grade of CIPN. Results: Thus far we have enrolled 276 patients with an average age of 63.69 years (±12.85 STDEV; Range; 25-91). Patients are predominantly of Caucasian heritage (80.8%) along with 18.1 % African American and 1.1% Asian heritage. Females constitute 53.26 % of the cohort. To date we have 150 patients with more than 24 months of follow-up and among these patients, 5.5% had no reported symptoms of CIPN. Of those with severe CIPN (NCCN grade 3) neuropathy, 71% had a reduction in GSH recycling of greater than or equal to 40% from pre-treatment level. The reduced glutathione recycling capacity preceded on-set of symptoms by approximately 4 weeks. The majority of patients demonstrating this pattern of glutathione recycling had persistence CIPN that lasted for 6-18 months before an improvement was noted in medical records. We are currently assessing the value of adding biomarkers for lipid peroxidation and/or myelin formation/maintenance to further improve the likelihood ratio and AUROC values for the test. Conclusions: This data suggests the importance of GSH recycling in the ability to predict risk of CIPIN. Patients whose pre-treatment baseline was less than 1 or progressively dropped by at least 40%, seem to be at most risk for CIPN. Further, this may predict persistence of CIPN even after cessation of chemotherapy. Most patients in this cohort received taxanes or platinum therapy. However, given the similarity in mechanism and results from an early assessment of lymphoma patients treated with vinca alkaloids that resulted in similar outcomes with reduced glutathione recycling capacity suggest the possible use of this test to predict CIPN among lymphoma patients. Disclosures No relevant conflicts of interest to declare.

Phytochemical and Pharmacological Properties of Catharanthus roseus (Vinca)

Vinca alkaloids obtained from Madagascar are a subset of drugs. Generally, they are naturally extracted from the Vinca rosea plant, Catharanthus roseus G, Don and show hyperglycemia activity as well as cytotoxic effects. It is used to treat various diseases such as diabetes, hypertension, cancer, asthma, inflammation, malaria, angiogenesis, brain imbalance, dysentery, and is also used as a disinfectant that occurs due to potent microorganisms. The vinca alkaloids are played an essential role to fight cancer disease. There are some major vinca alkaloids in clinical use: Vinblastin, Vincristine, Vindesine, tabersonine, vinorelbine, and Vinpocetine, etc. The flowers juice of Vinca rosea is utilized to treat several skin problems e.g. acne, eczema, and dermatitis. According to our opinion that it may be help scientists, ayurvedic practitioners, pharmacognosists, botanists, researchers, and students who are active in the field of medicinal plants research.

Ultrasound-Microbubble Combined Treatment with Vinca Alkaloids in Prostate Cancer Cells

Therapeutic efficacy of chemotherapy is highly dependent on the ability to deliver drug molecules across tissue and cellular barriers. Ultrasound stimulated microbubbles (USMB) have been shown to enhance the delivery and cytotoxicity of various classes of chemotherapeutic agents. Here, the application of USMB in combination with the chemotherapeutic class vinca alkaloids is investigated. Specifically, vinorelbine tartrate (VRL) and vinblastine sulfate (VBL) of the vinca alkaloid class, which to the best of our knowledge have not been reported in combination with USMB, were used in this study. Cell viability analysis demonstrated that USMB does not enhance the cytotoxicity of either drug. VRL+USMB showed to have an additive response in cell death, whereas VBL+USMB resulted in an additive effect at a low peak negative pressure, and antagonistic at higher pressures. This work suggests that the mechanism of uptake is an important factor in determining the effectiveness of a chemotherapy drug with USMB treatment.

Ultrasound-Microbubble Combined Treatment with Vinca Alkaloids in Prostate Cancer Cells

Therapeutic efficacy of chemotherapy is highly dependent on the ability to deliver drug molecules across tissue and cellular barriers. Ultrasound stimulated microbubbles (USMB) have been shown to enhance the delivery and cytotoxicity of various classes of chemotherapeutic agents. Here, the application of USMB in combination with the chemotherapeutic class vinca alkaloids is investigated. Specifically, vinorelbine tartrate (VRL) and vinblastine sulfate (VBL) of the vinca alkaloid class, which to the best of our knowledge have not been reported in combination with USMB, were used in this study. Cell viability analysis demonstrated that USMB does not enhance the cytotoxicity of either drug. VRL+USMB showed to have an additive response in cell death, whereas VBL+USMB resulted in an additive effect at a low peak negative pressure, and antagonistic at higher pressures. This work suggests that the mechanism of uptake is an important factor in determining the effectiveness of a chemotherapy drug with USMB treatment.

PLANT-DERIVED CHEMOTHERAPEUTICS DRUGS FOR CANCER CHEMOTHERAPY

Cancer chemotherapeutic drugs acts in different manner to kill malignant cells. Most of the anticancer drugs available in clinical practice to treat cancer patients, are natural products including whole plant extract, crude plant extracts, isolated constituents, plant –based drug formulations etc. These natural compounds have been a basis for the development of several drugs against cancer. Agents such as topotecan, taxol, vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine), are important anticancer agents in widespread clinical use. Other agents, such as combretastatin, flavopiridol, betulinic acid were shown to have anti-tumor effects in both in vitro and in vivo experiments. In this review, we aim to make a brief description of classical plant-derived chemotherapeutics drugs and also to highlight the importance of these natural compounds in the development of new potential drugs in cancer treatment.