1,721,151 research outputs found
Inibitori di PARP come modulatori della resistenza alla chemioterapia
No full textPoly(ADP-ribose) polymerase (PARP) inhibitors as modulators of tumor drug resistance to chemotherapy.
Poly(ADP-ribose) polymerase (PARP) inhibitors are a promising class of anticancer agents currently in clinical trials either in combination with chemotherapy [e.g., the methylating compound temozolomide (TMZ), the topoisomerase I (TOPO I) poisons irinotecan (CPT-11) or topotecan] and radiotherapy or as monotherapy. In fact, PARP inhibitors exert cytotoxic effects as single agents in BRCA mutated tumors, which are defective in the homologous recombination repair (HR) of DNA double strand breaks (DSBs). In preclinical models we have demonstrated that PARP inhibitors enhance the antitumor activity of TMZ or of TOPO I inhibitors especially in mismatch repair (MMR) deficient tumors, including colorectal cancer that is frequently characterized by MMR dysfunction. Moreover, the PARP inhibitor GPI 15427 increases the efficacy also of CPT-11 and TMZ combination against MMR deficient colon cancer in vitro and in tumor xenografts. hMLH1 is mainly involved in the processing of O6-methylguanine:C/T mispairs responsible for the cytotoxic effects of TMZ. Recently, it has been suggested that MSH3 might be involved in the repair of DSBs induced by intra-strand cross-links provoked by platinum derivatives through the intervention of HR. The role of the different MMR components in the susceptibility of colon cancer cells to TOPO I poisons have not been clarified, yet.
The human colon cancer cell lines HCT116 (known to have a homozygous mutation in the MMR hMLH1 gene on chromosome 3 and homozygous frameshift mutations in the MMR hMSH3 gene on chromosome 5), the HCT116 derived cell lines in which only the wild-type hMLH1 (HCT116+3) or both the wild-type hMLH1 and hMSH3 genes (HCT116+3+5) have been replaced, via chromosome transfer, were used to test their susceptibility to anticancer drugs with different mechanisms of action. The hMLH1 and hMSH3 deficient HCT116 cells and the HCT116+3+5 cells were more sensitive to SN38 (the active metabolite of CPT-11) than HCT116+3 cells that, instead, were highly sensitive to TMZ. Interestingly, the hMLH1 and hMSH3 proficient HCT116+3+5 cells were more resistant to oxaliplatin than the other cell lines. HCT116, characterized by a higher PARP-1 expression with respect to the other cell lines, were the most sensitive to the PARP inhibitor GPI 15427 as single agent. Stable silencing of PARP-1 expression resulted in increased chemosensitivity. The results suggest that that hMLH1, hMSH3 or PARP-1 status may predict differential sensitivity to chemotherapeutic agents
Doping and Cancer
No full textAnabolic steroids and peptides are utilized to increase the performance of athletes of professional or amateur sports. The use of some of these agents has significantly grown and has been extended also to non athletes with the aim to improve appearance or to counteract ageing. Besides the well documented side effects of hormones or growth factors, experimental evidences have warned about the potential risk of cancer development and progression. Anabolic steroids have been described to provoke serious adverse effects to the liver, including tumors; treatment with growth hormone (GH) and high levels of its mediator insulin-like growth factor-1 (IGF-1) have been associated with colon, breast, and prostate cancers. Actually, IGF-1 promotes cell cycle progression and inhibits apoptosis either by triggering other growth factors or by interacting with pathways which have an established role in carcinogenesis and cancer promotion. Thus, it is likely that GH/IGF-1 might accelerate carcinogenesis, although a direct cause-effect relationship has not been proven, yet. Circumstantial evidences in support to this fear come from in vitro and/or animal studies, but also from epidemiological observations within the general population in patients with an excess of production of GH or in patients chronically treated with GH/IGF-1 for various pathologies.
More recently the finding of the expression of erythropoietin (Epo) receptor (R) in cancer cells has suggested the possibility that recombinant Epo may exert direct effects on tumor cells such as stimulation of proliferation and angiogenesis or inhibition of apoptosis. The presence of an autocrine-paracrine Epo/EpoR loop in tumors and the possible effects of Epo on tumor microenvironment and angiogenesis are consistent with the involvement of Epo/EpoR signalling in cancer.
Therefore, the potential risk of developing cancer after treatment with hormone/growth factors deserves careful evaluation and further studies are requested
Una medicina che cambia: l’approccio all’ipercolesterolemia
No full textUna concentrazione elevata di colesterolo nel plasma può essere di natura ereditaria oppure conseguente a una dieta ricca di calorie e di acidi grassi saturi. L’aumento dei livelli di colesterolo nel sangue, che spesso è accompagnato da un’alterazione dei lipidi circolanti o dislipidemia, l’eccessivo accumulo di grasso nel tessuto sottocutaneo, uno stile di vita caratterizzato da inattività fisica e da una dieta poco sana contribuiscono allo svilupparsi di patologie aterosclerotiche coronariche. Tali patologie, o coronaropatie insieme con altre patologie cardiovascolari sono la principale causa di morte nel mondo.
In questo capitolo vengono presi in esame i diversi fattori di rischio che possono contribuire ad aumentare la probabilità di incorrere in eventi cardiovascolari come infarti ed ictus. Lo stile di vita, il tipo di dieta da seguire e l’attività fisica da svolgere sono importantissimi per ridurre la percentuale di rischio cardiovascolare. Per quanto concerne l’approccio farmacologico, sono oggi disponibili varie classi di farmaci che con diverso meccanismo d’azione riducono i livelli plasmatici di colesterolo. Ciononostante, sicuramente le statine rappresentano la classe di farmaci più impiegata e per la quale sono state prodotte più numerose e solide evidenze riguardo all’efficacia nel tenere sotto controllo non solo la colesterolemia, ma anche il rischio dell’evenienza di malattie cardio- e cerebro-vascolari.
Alla fine del 2013 l’American College of Cardiology (ACC) e l’American Heart Association (AHA) hanno emanato nuove linee guida per il “Trattamento dei livelli di colesterolo nel sangue per ridurre il rischio di patologie cardiovascolari su base atero-sclerotica nell’adulto”. Recentemente si è assistito ad accesi dibattiti sui presupposti e sulle conseguenze delle linee guida ACC/AHA. La principale fonte di controversia riguarda la domanda a cui le raccomandazioni in esse contenute cercano di dare risposta, ovvero “il paziente ha un rischio di sviluppare malattie cardiovascolari così elevato da ottenere beneficio dalla terapia con statine?" Scopo di questo capitolo è impostare un ragionamento sull’approccio personalizzato, per la correzione/riduzione dei fattori di rischio che aumentano la probabilità di incorrere in eventi cardiovascolari sulla base dalle nuove linee guida dell’ACC/AHA
L’attività fisica come terapia complementare: l’esempio delle malattie oncologiche
No full textRecentemente numerosi studi clinici ed epidemiologici hanno riportato i benefici dell’esercizio fisico nella prevenzione e nel trattamento di diverse patologie croniche. L’attività fisica regolare è sempre più frequentemente proposta come supporto ai trattamenti farmacologici convenzionali (terapia complementare). L’incremento di attività fisica, una dieta sana l’astensione dal fumo sono modificazioni dello stile di vita (Lifestyle Medicine) suggerite nelle linee guida per la prevenzione del rischio cardiovascolare negli stati di ipercolesterolemia e sono consigliate nell’ipertensione, nell’obesità, nel diabete e, a supporto della terapia convenzionale, per alcune forme di cancro. Molti approcci di medicina complementare che includono l’attività fisica vengono utilizzati per il trattamento di malattie croniche degenerative, muscoloscheletriche, metaboliche, artritiche, oncologiche, neurologiche (emicrania), ansia e insonnia. L’incremento dell’attività fisica include tecniche/terapie motorie generalmente insegnate da un istruttore o da un medico.
Diversi studi clinici ed epidemiologici hanno dimostrato che l’attività fisica può essere molto utile per il controllo della sintomatologia di malattie croniche e per migliorare la qualità della vita nei pazienti sottoposti a terapia convenzionale. In particolare è interessante rilevare che studi clinici randomizzati hanno dimostrato gli effetti positivi dell’attività fisica nella prevenzione e nella terapia integrata del cancro della mammella e del colon
Temozolomide: An Update on Pharmacological Strategies to Increase its Antitumour Activity
No full textTemozolomide (TMZ) is a methylating agent with promising antitumour activity against primary or secondary
brain tumours. Through the generation of a reactive intermediate, TMZ interacts with DNA at different base site positions,
generating a wide spectrum of methyl adducts represented mainly by N-methylpurines (70%) while, at a lesser extent, by
N3-methyladenine (9%) and O6-methylguanine (5%). The antitumour activity of TMZ has been primarily attributed to O6-
methylguanine, since tumour cell sensitivity inversely correlates with the levels of O6-alkylguanine DNA alkyltransferase
and requires an intact mismatch repair system.
Even though the pharmacokinetics properties, favourable toxicity profile and antitumour activity against a broad range of
tumour types render TMZ an attractive agent in oncology, resistance to the methylating agent occurs relatively often and
strongly affects the rate and durability of clinical response in cancer patients. Thus, different strategies aimed at
counteracting resistance and increasing the efficacy of TMZ have been designed and for many of them investigation is
still underway. Herein, we provide an update on the latest findings of preclinical and clinical studies on TMZ in
combination with resistance or biological modulators and anticancer drugs with different mechanisms of action
Recent Approaches to Improve the Antitumor Efficacy of Temozolomide.
No full textTemozolomide (TMZ) is an oral anticancer agent approved for the treatment of newly diagnosed glioblastoma in combination with radiotherapy. Moreover, TMZ has shown comparable efficacy with respect to dacarbazine, the reference drug for metastatic melanoma. Due to its favorable toxicity and pharmacokinetic profile, TMZ is under clinical investigation for brain metastasis from solid tumors and refractory leukemias. TMZ interacts with DNA generating a wide spectrum of methyl adducts mainly represented by N-methylpurines. However, its antitumor activity has been mainly attributed to O(6)-methylguanine, since tumor cell sensitivity inversely correlates with the levels of O(6)-alkylguanine DNA alkyltransferase and requires an intact mismatch repair system. Therefore, an increasing number of studies have been performed in order to identify patients who will benefit from TMZ treatment on the basis of their molecular/genetic profile. Unfortunately, resistance to the methylating agent occurs relatively often and strongly affects the rate and durability of the clinical response in cancer patients. Thus, different approaches have been developed to abrogate resistance or to increase the efficacy of TMZ and for many of them investigation is still underway. Herein, we provide an overview on the recent findings of preclinical and clinical studies on TMZ in combination with inhibitors of DNA repair, chemotherapeutic drugs with different mechanisms of action or radiotherapy, anti-angiogenic agents and other biological modulators
Is photodecomposition more important than metabolic activation for the antitumor activity of dacarbazine (multiple letters)
No full textLev et al. (1) clearly demonstrate that the antitumor agent dacarbazine (DTIC) causes melanoma cells to secrete interleukin (IL)-8 and vascular endothelial growth factor (VEGF). The authors suggest that cytokine overexpression might render tumor cells resistant to DTIC, which is presently considered the reference drug for the treatment of malignant melanoma.
The study has been entirely conducted using light-activated DTIC without considering that DTIC requires metabolic activation by liver microsomes to generate 5(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which is responsible of the alkylation of nucleic acids (2). In particular, O6-methylaguanine is regarded as the major cytotoxic lesion produced by the active metabolite of DTIC (2). In fact, tumor cells expressing high levels of the O6-alkylguanine DNA alkyltransferase (AGT) are resistant to DTIC and to temozolomide, which spontaneously decomposes in aqueous solution to generate the methylating species MTIC (3, 4).
Although the importance of light protection for DTIC, to avoid toxicity due to photodecomposition products, is still controversial, it is instead well established that the antitumor activity of DTIC is mainly the result of DNA methylation.
Therefore, to assess whether IL-8 and VEGF expression in melanoma cells might limit the efficacy of DTIC, it would have been certainly more interesting to evaluate the influence of MTIC-induced DNA methylation rather than analyzing the effects of photodecomposition products, which might not substantially contribute to the antitumor effects of DTIC
Challenging resistance mechanisms to therapies for metastatic melanoma
No full textMelanoma is the most aggressive form of skin cancer and, if spread outside the epidermis, has a dismal prognosis. Before the approval of the anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody ipilimumab and the BRAF inhibitors vemurafenib and dabrafenib, no other agents had demonstrated better results in terms of overall survival than the DNA-methylating compound dacarbazine (or its oral analog temozolomide). However, most patients with metastatic melanoma do not obtain long-lasting clinical benefit from ipilimumab and responses to BRAF inhibitors are short lived. Thus, combination therapies with inhibitors of DNA repair (e.g., poly(ADP-ribose) polymerase [PARP] inhibitors), novel immunomodulators (monoclonal antibodies against programmed death-1 [PD-1] or its ligand PD-L1), targeted therapies (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase [ERK] kinase [MEK] or phosphatidylinositol 3-kinase [PI3K]/AKT/mammalian target of rapamycin [mTOR] inhibitors) or antiangiogenic agents are currently being investigated to improve the efficacy of antimelanoma therapies. This review discusses the implications of simultaneously targeting key regulators of melanoma cell proliferation/survival and immune responses to counteract resistance
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