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.

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.

“Enhancement of Vincristine Under In Vitro Culture of Catharanthus Roseus Supplemented With Alternaria Sesami Endophytic Fungal Extract As Biotic Elicitor”

Vincristine, one of the major vinca alkaloid of Catharanthus roseus(L.) G. Don. (Apocynaceae) was enhanced under in vitro culture of C.roseus using fungal extract of an endophyte Alternaria sesami isolated from the surface-sterilized root cuttings of C.roseus. Vindoline, a precursor molecule of Vincristine was detected for the first time from the fungal endophyte A.sesami which was used as biotic elicitor to enhance Vincristine content in the C.roseus callus.It was identified using high performance liquid chromatography and mass spectroscopy techniques by matching retention time and mass data with reference molecule. Supplementing heat sterilized A.sesami endophytic fungal culture extract into callus culture medium of C. roseus enhanced the Vincristine content in C. roseus callus by 21.717% after 105 day culture.

Analysis of chemotherapy-induced peripheral neuropathy using the Japanese Adverse Drug Event Report database

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event associated with several antineoplastic drugs; however, the precise risks and time course of reactions of particular drugs are not clearly understood. The aim of this study was to evaluate the relationship between anticancer agents and CIPN development using data from the Japanese Adverse Drug Event Report (JADER) database and to characterize the time-to-onset and outcomes of CIPN. Chemotherapy-induced peripheral neuropathy was defined using the Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence interval for signal detection. Data of nine Anatomical Therapeutic Chemical (ATC) drug categories correlated with CIPN development, in addition to the data of the time-to-onset and outcomes. Among 622,289 reports in the JADER database from April 2004 to March 2020, there were 1883 reports of adverse events corresponding to peripheral neuropathy. The ROR (95% confidence interval) for vinblastine, sorbent-based paclitaxel (sb-PTX), oxaliplatin, and bortezomib was 20.4 (12.5–33.4), 13.6 (11.9–15.7), 26.2 (23.6–29.1), and 30.8 (26.6–35.8), respectively. The median duration (interquartile range) to CIPN development after the administration of vinca alkaloids and analogues, taxanes, platinum compounds, and monoclonal antibodies was 11.0 (5.0–46.5), 22.5 (6.0–82.5), 22.0 (6.0–68.5), and 32.5 (11.3–73.8) days, respectively. The median duration (interquartile range) of sb-PTX and nanoparticle albumin-bound (nab)-PTX was 35.0 (7.0–94.0) and 5.5 (3.0–29.3) days, respectively. Our analysis of records in the JADER database revealed several drugs associated with a high risk for CIPN development. In particular, the development of CIPN after vinca alkaloid administration should be closely monitored for 2 weeks after administration. CIPN caused by nab-PTX showed significantly faster onset than that by sb-PTX. Patients who receive taxanes or monoclonal antibodies often do not show an improvement; accordingly, early treatment is required.

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.

Development of a Cell Suspension Culture System for Promoting Alkaloid and Vinca Alkaloid Biosynthesis Using Endophytic Fungi Isolated from Local Catharanthus roseus

Cell and tissue cultures of Catharanthus roseus have been studied extensively as an alternative strategy to improve the production of valuable secondary metabolites. The purpose of this study was to produce C. roseus callus and suspension cell biomass of good quality and quantity to improve the total alkaloids and bis-indole alkaloids. The young stem derived-callus of C. roseus variety Quang Ninh (QN) was grown on MS medium supplemented with 1.5 mg/L 2,4-dichlorophenoxyacetic acid (2,4-D) plus 1.5 mg/L kinetin, and the growth rate increased by 67-fold after 20 days. The optimal conditions for maintaining the cell suspension culture were 150 mg/50 mL cell inoculum, a medium pH of 5.5 and a culture temperature of 25 °C. The low alkaloid content in the culture was compensated for by using endophytic fungi isolated from local C. roseus. Cell extracts of endophytic fungi—identified as Fusarium solani RN1 and Chaetomium funicola RN3—were found to significantly promote alkaloid accumulation. This elicitation also stimulated the accumulation of a tested bis-indole alkaloid, vinblastine. The findings are important for investigating the effects of fungal elicitors on the biosynthesis of vinblastine and vincristine, as well as other terpenoid indole alkaloids (TIAs), in C. roseus QN cell suspension cultures.

Management of Systemic Lupus Erythematosus complicated with Refractory Immune Thrombocytopenic Purpura and Pulmonary Artery Hypertension

The coexistence of immune thrombocytopenia (ITP) and pulmonary artery hypertension (PAH) is rarely observed as the initial manifestation of systemic lupus erythematosus (SLE), often leading to delayed diagnosis and poor outcome. We presented the case of an 18-year-old female of Asian origin with severe ITP and PAH as the initial manifestation of SLE. The patient was successfully treated with a combination of methylprednisolone, mycophenolate mofetil, sildenafil, and vinca alkaloid (vincristine). This case provided the opportunity to increase awareness of an uncommon association between SLE complicated with ITP and PAH and suggest a positive impact of early diagnosis and appropriate treatment on the patient’s outcome. The use of vincristine was considered as per the guideline on refractory ITP before referral for splenectomy.