Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of ...these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer.
Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from ...single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
Abstract Chemotherapy has already proven widely effective in the treatment of cancer, occupying a prominent place in the current therapeutic arsenal. However, in recent years, there has been a ...plateau in the evolution of the clinical results obtained with this modality treatment. In some cases, the limitations of chemotherapy observed during the early days still apply. These facts forced us to do a thorough analysis of what happened in the past 60 years. We have observed that each major advance obtained in this field was based on empirical clinical observations. We thus believe that the current results of old or new agents can only be improved by understanding the natural history of each specific cancer subtype at the clinical level and by overcoming the physiological barriers involved in chemotherapy failure. This strategy will surely allow us to enlarge the list of curable cancers by chemotherapy.
There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively ...in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
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► Trabectedin is a recently approved antitumor agent of marine origin ► Trabectedin activates caspase-8-dependent apoptosis exclusively in myelomonocytes ► In vivo trabectedin reduces monocytes and TAM, and related angiogenesis ► Depletion of TAM is a key component of the antitumor efficacy of trabectedin
► Distinction between likes and dislikes makes the transcription of consumers’ opinions easier. ► Chi-square per cell allows a deeper analysis of contingency table of comments per product. ► In ...absence of a trained panel, this methodology can be used to access consumers’ sensory key drivers.
This study compares the analysis of consumer’s comments resulting from a hedonic test as an alternative to the traditional internal preference mapping. During a consumer test, 87 apple consumers first evaluated six different Golden apple batches on a hedonic scale and then answered to the non-mandatory open-ended questions stating separately what they liked and disliked from each batch. In parallel, an expert panel described the sensory profiles of the studied products.
To compare the results obtained by the two studied methods the RV coefficient was calculated and was found to be 0.8656 (p=0.011). Therefore, the information obtained by the comment analysis of likes and dislikes was similar to that resulting from sensory characterization done by the trained panel. With both methods, crunchiness and sweetness appeared as main sensory preference key drivers, while mealiness was not appreciated. At the same time, some characteristics such as juiciness appeared important for consumers but it was not a significant discriminant attribute for the trained panel.
A new method, the Chi-square per cell, was used to deeply analyze the contingency table of the main modalities used by consumers allowing the identification of the significant modalities which described each apple liking. Finally, the distinction between likes and dislikes made the transcription of consumers’ opinions easier, without a need of interpretation on behalf of the transcoder.
Flavor pairing is the base of food product development. Moreover, foodstuffs are rarely consumed in an isolated manner, needing to study the sensory experience of food-beverage and food-food ...combinations. The field of flavor combination includes: the intrinsic arrangement of ingredients within a recipe; the combination of food products among them and with beverages; and the preparation of a whole meal. This review goes over the different definitions used to describe pairing and the sensory methods proposed in the literature.
Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of ...patients with relapsed platinum-sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti-cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment.
Cytotoxic nucleoside analogues are clinically important anticancer drugs. These agents behave as antimetabolites, compete with physiologic nucleosides, and, consequently, interact with a large number ...of intracellular targets to induce cytotoxicity. Nucleoside analogues share some general common characteristics, namely in terms of requiring transport by specific membrane transporters and intracellular metabolism. However these compounds differ in regard to the preferential interaction with certain targets which may explain why some compounds are more effective against rapidly proliferating tumours and others on neoplasia with a more protracted evolution. Purine and pyrimidine analogues are widely used not only as antileukaemic agents, but also as cytotoxic agents to treat solid tumours. However, the clinical use of these compounds is limited by important side-effects and primary or acquired drug resistance. Thus, there is an unmet medical need for the development of new antimetabolites and for technologies allowing a more suitable and effective administration of nucleoside analogues for the treatment of cancer patients. Here, we will review literature data concerning the recent development of novel purine nucleoside analogues (clofarabine, nelarabine and forodesine) and pyrimidine nucleoside analogues (troxacitabine, sapacitabine, CP-4055, 3-C-ethynylcytidine and 5-azapyrimidines) that are in evaluation at the clinical level.
To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized ...three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro. Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.
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