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Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug-drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer.

Introduction: Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity., Methods: A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol.", Results: The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children., Conclusions: Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.

The clinical use of antineoplastic drugs can be limited by different drug-induced toxicities. Of these, renal dysfunction may be one of the most troublesome in that it can be cumulative and in general is only partially reversible with the discontinuation of the treatment. Renal toxicity may be manifested as a reduction of the glomerular filtration rate, electrolyte imbalances, or acute renal failure. Careful assessment of renal function has to be performed taking into account that the impairment of renal function is initially silent and only later may be clinically dramatic. When clinically indicated, the reduction or, in cases of severe nephrotoxicity, the suspension of chemotherapy should be considered to avoid the progressive deterioration of the compromised glomerular and/or tubular function., (© 2017 The British Pharmacological Society.)

Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy. Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.

Epileptic seizures are a common clinical problem in children with brain tumors. The conventional antiepileptic drugs (AEDs) permit a good seizure control in most of these children. An emerging problem is the possible interactions between AEDs and chemotherapeutic drugs, because many of these drugs are metabolized by the cytochrome P450. The aim of this article is to propose a novel therapeutic approach for new-onset epilepsy in children with brain tumors. Among the new AEDs not metabolized by the P450 system, levetiracetam seems to be a promising AED owing to its pharmacokinetic features, efficacy, and safety., ((c) 2009 Wiley-Liss, Inc.)

Hypersensitivity reactions to carboplatin are rare but sometimes life-threatening events may occur requiring discontinuation of treatment. In our study, we describe clinical features and diagnostic procedures of carboplatin-associated reactions in children affected by low-grade astrocytoma and treated with multiple courses of carboplatin. In 6 out of 29 children, we reported allergic events. We also report a desensitization protocol for carboplatin administration, which allowed the patients to receive effective treatment without adverse reactions.

Simple Summary: This review is divided into two parts. The first analyzes the mechanisms of two important cellular pathways that are involved in tumoral proliferation, differentiation, migration, and angiogenesis: RAS/RAF/MEK/MAPK and PI3K/AKT/mTOR. The second part focuses on the currently available experience regarding targeted therapies against the mitogen-activated protein kinase (MAPK) pathway in pediatric CNS tumors, with the hope of offering a practical guide for consultation. BRAF is a component of the MAPK and PI3K/AKT/mTOR pathways that play a crucial role in cellular proliferation, differentiation, migration, and angiogenesis. Pediatric central nervous system tumors very often show mutations of the MAPK pathway, as demonstrated by next-generation sequencing (NGS), which now has an increasing role in cancer diagnostics. The MAPK mutated pathway in pediatric CNS tumors is the target of numerous drugs, approved or under investigation in ongoing clinical trials. In this review, we describe the main aspects of MAPK and PI3K/AKT/mTOR signaling pathways, with a focus on the alterations commonly involved in tumorigenesis. Furthermore, we reported the main available data about current BRAF and MEK targeted therapies used in pediatric low-grade gliomas (pLLGs), pediatric high-grade gliomas (pHGGs), and other CNS tumors that often present BRAF or MEK mutations. Further molecular stratification and clinical trial design are required for the treatment of pediatric CNS tumors with BRAF and MEK inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: In this paper we perform an introduction about pregnancy-associated cancer (PAC) and transplacental passage of antineoplastic agents. Furthermore, we describe therapeutic use and potential toxic effects of chemotherapeutic drug (alkylating agents, antimetabolites agents, anthracyclines, topoisomerase inhibitors, antimitotic agents, actinomycin-D, bleomycin) and targeted agents during pregnancy. This manuscript may be a useful and practical guide for the management of PAC, which is a challenge for clinicians that have to consider alike maternal benefits and fetal potential risks correlated to the antineoplastic treatment. The incidence of PAC is relatively infrequent among pregnant women. However, it has gradually increased in recent years, becoming a challenging area for clinicians that should take into account in the same way maternal benefits and fetal potential risks correlated to the antineoplastic treatment. None of the antineoplastic drugs is completely risk-free during the pregnancy, the timing of exposure and transplacental transfer properties influence the toxicity of the fetus. Despite the lack of guidelines about the management of PAC, several studies have described the use and the potential fetal and neonatal adverse events of antineoplastic drugs during pregnancy. We provide a review of the available literature about the transplacental passage and fetal effects of chemotherapy and targeted agents, to guide the clinicians in the most appropriate choices for the management of PAC. [ABSTRACT FROM AUTHOR]

Patients with cancer receive multidrug therapy. Antineoplastic agents and supportive care drugs are often administered together, leading to potential drug-drug interactions. These interactions may have significant clinical implications in terms of toxicity or a decrease in the efficacy of the treatment administered. Here, we focus on the role of azoles and their main pharmacokinetic interactions with the principal classes of drugs used in pediatric oncology. The co-administration of azoles and antineoplastic agents, corticosteroids, immunosuppressants, antacids, antiemetics, antiepileptic drugs and analgesics was investigated, and a practical guide on the management of these drugs when administered together is provided. [ABSTRACT FROM AUTHOR]

Background: The prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient. Methods: A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–8; (2) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–8; (3) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–10; (4) TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7years. Results: None of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3. Conclusion: The recommended phase II dose in children is TMZ 150mg/m2 on days 1–5 and VP-16 50mg/m2 on days 1–10 every 28d. The combination was well tolerated and demonstrated antitumour activity. [Copyright &y& Elsevier]