Is there scope for better individualisation of anthracycline cancer chemotherapy?

Sallustio, Benedetta C.; Boddy, Alan V.

doi:10.1111/bcp.14628

Cited by 30 publications

(26 citation statements)

References 103 publications

(283 reference statements)

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“…Extrapolating further, could dabrafenib be cardioprotective in patients with cancer, undergoing treatments with established cardiotoxicity (e.g. anthracyclines [ 40 ])? Moreover, would a cancer environment compromise the cardioprotective effects of dabrafenib on the heart?…”

Section: Discussionmentioning

confidence: 99%

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

et al. 2021

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Raf kinases signal via extracellular signal-regulated kinases 1/2 (ERK1/2) to drive cell division. Since activating mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) are highly oncogenic, BRAF inhibitors including dabrafenib have been developed for cancer. Inhibitors of ERK1/2 signalling used for cancer are cardiotoxic in some patients, raising the question of whether dabrafenib is cardiotoxic. In the heart, ERK1/2 signalling promotes not only cardiomyocyte hypertrophy and is cardioprotective but also promotes fibrosis. Our hypothesis is that ERK1/2 signalling is not required in a non-stressed heart but is required for cardiac remodelling. Thus, dabrafenib may affect the heart in the context of, for example, hypertension. In experiments with cardiomyocytes, cardiac fibroblasts and perfused rat hearts, dabrafenib inhibited ERK1/2 signalling. We assessed the effects of dabrafenib (3 mg/kg/d) on male C57BL/6J mouse hearts in vivo. Dabrafenib alone had no overt effects on cardiac function/dimensions (assessed by echocardiography) or cardiac architecture. In mice treated with 0.8 mg/kg/d angiotensin II (AngII) to induce hypertension, dabrafenib inhibited ERK1/2 signalling and suppressed cardiac hypertrophy in both acute (up to 7 d) and chronic (28 d) settings, preserving ejection fraction. At the cellular level, dabrafenib inhibited AngII-induced cardiomyocyte hypertrophy, reduced expression of hypertrophic gene markers and almost completely eliminated the increase in cardiac fibrosis both in interstitial and perivascular regions. Dabrafenib is not overtly cardiotoxic. Moreover, it inhibits maladaptive hypertrophy resulting from AngII-induced hypertension. Thus, Raf is a potential therapeutic target for hypertensive heart disease and drugs such as dabrafenib, developed for cancer, may be used for this purpose.

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Section: Discussionmentioning

confidence: 99%

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

et al. 2021

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“…However, it is unlikely that this step is performed in exactly the same manner by all IRs, thereby increasing variability. Because the composition of the emulsion is not standardized, there are large variations in preparation technique, aqueous-to-lipid phase ratio, aqueous phase composition, and injectability properties [ 78 , 93 ]. All these parameters affect the drug release rates [ 93 ] and can further introduce variability between different studies.…”

Section: Current Drug Performancementioning

confidence: 99%

“…This probably contributes to the fact that there is still no consensus regarding the optimal chemotherapeutic drug for TACE. Despite more than six decades of experience in the clinical use of anthracyclines, their mechanism(s) remain mainly empirical [ 93 ].…”

Section: Current Drug Performancementioning

confidence: 99%

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

Barbier

Heindryckx

Lennernäs

2021

IJMS

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Because diagnostic tools for discriminating between hepatocellular carcinoma (HCC) and advanced cirrhosis are poor, HCC is often detected in a stage where transarterial chemoembolization (TACE) is the best treatment option, even though it provides a poor survival gain. Despite having been used worldwide for several decades, TACE still has many limitations. First, there is a vast heterogeneity in the cellular composition and metabolism of HCCs as well as in the patient population, which renders it difficult to identify patients who would benefit from TACE. Often the delivered drug does not penetrate sufficiently selectively and deeply into the tumour and the drug delivery system is not releasing the drug at an optimal clinical rate. In addition, therapeutic effectiveness is limited by the crosstalk between the tumour cells and components of the cirrhotic tumour microenvironment. To improve this widely used treatment of one of our most common and deadly cancers, we need to better understand the complex interactions between drug delivery, local pharmacology, tumour targeting mechanisms, liver pathophysiology, patient and tumour heterogeneity, and resistance mechanisms. This review provides a novel and important overview of clinical data and discusses the role of the tumour microenvironment and lymphatic system in the cirrhotic liver, its potential response to TACE, and current and possible novel DDSs for locoregional treatment.

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“…Accordingly, troponin T and other myocardial damage biomarkers monitoring could facilitate the early identification of vulnerable patients. Such approaches warrant deeper investigation as a reasonable predictive measure (36).…”

Section: Cardiotoxicitymentioning

confidence: 99%

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

2021

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During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

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Is there scope for better individualisation of anthracycline cancer chemotherapy?

Cited by 30 publications

References 103 publications

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

The anti-cancer drug dabrafenib is not cardiotoxic and inhibits cardiac remodelling and fibrosis in a murine model of hypertension

Limitations and Possibilities of Transarterial Chemotherapeutic Treatment of Hepatocellular Carcinoma

Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?

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