A cholesterol-rich microemulsion or nanoparticle termed LDE concentrates in cancer tissues after injection into the bloodstream. Here the cytotoxicity, pharmacokinetics, toxicity to animals and therapeutic action of a paclitaxel lipophilic derivative associated to LDE is compared with those of the commercial paclitaxel. Results show that LDE-paclitaxel oleate is stable. The cytostatic activity of the drug in the complex is diminished compared with the commercial paclitaxel due to the cytotoxicity of the vehicle Cremophor EL used in the commercial formulation. Competition experiments in neoplastic cultured cells show that paclitaxel oleate and LDE are internalized together by the LDL receptor pathway. LDE-paclitaxel oleate arrests the G(2)/M phase of cell cycle, similarly to commercial paclitaxel. Tolerability to mice is remarkable, such that the lethal dose (LD(50)) was ninefold greater than that of the commercial formulation (LD(50) = 326 microM and 37 microM, respectively). LDE concentrates paclitaxel oleate in the tumor roughly fourfold relative to the normal adjacent tissues. At equimolar doses, the association of paclitaxel oleate with LDE results in remarkable changes in the drug pharmacokinetic parameters when compared to commercial paclitaxel (t(1/2)=218 min and 184 min, AUC=1,334 microg h/ml and 707 microg h/ml and CL=0.125 ml/min and 0.236 ml/min, respectively). Finally, the therapeutic efficacy of the complex is pronouncedly greater than that of the commercial paclitaxel, as indicated by the reduction in tumor growth, increase in survival rates and % cure of treated mice. In conclusion, LDE-paclitaxel oleate is a stable complex and compared with paclitaxel toxicity is considerably reduced and activity is enhanced, which may lead to improved therapeutic index in clinical use.

Association with LDE preserves the cytotoxicity of carmustine and markedly diminishes its side effects.

Recebido em 11/9/09; aceito em 2/2/10; publicado na web em 18/6/10 CHEMISTRY AND PHARMACOLOGY OF ANTINEOPLASIC CHEMOTERAPEUTICAL DERIVATIVES FROM PLANTS. This review demonstrates the importance of plants as sources of molecules used in anticancer therapies. The approach is performed by relating the active molecules to their origins, details, mechanisms of action, structure-activity relationship and chemical characteristics of chemotherapeutical medicines. It was also described the development of anticancer agents from plants by the pharmaceutical industry and the difficulties to release these compounds as a trademark. These include the well known paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vindesine, etoposide, teniposide, and other molecules that are undergoing clinical trials.Keywords: plant antineoplasics; chemotherapic; cancer. INTRODUÇÃOSubstâncias orgânicas originadas de fontes naturais há muito tempo são utilizadas no tratamento de inúmeras enfermidades no ser humano. Grande parte dos medicamentos encontrados no mercado é derivada direta ou indiretamente de vegetais, micro-organismos, organismos marinhos, vertebrados e invertebrados terrestres.1,2 Analisando os medicamentos disponibilizados no mercado entre 1981 e 2002, observa-se que 28% destes possuem princípios ativos isolados de produtos naturais ou semissintéticos, ao passo que 24% são sintéticos com grupos farmacofóricos baseados em estruturas de produtos naturais. Portanto, mais da metade dos novos medicamentos lançados no referido período são derivados de produtos naturais, mostrando que essa fonte é muito importante nos estudos de desenvolvimento de novos medicamentos. 1,3 Os vegetais representam as maiores fontes de substâncias ativas que podem ser usadas na terapêutica, devido à grande diversidade estrutural de metabólitos produzidos e, talvez, a fonte mais antiga de medicamentos para o homem. Na busca de novos medicamentos originados de plantas são envolvidos diversos conhecimentos que vão desde aspectos agronômicos, botânicos, químicos, farmacológicos e toxicológicos. 4 Metodologias recentes cada vez mais modernas de isolamento e identificação de compostos de fontes naturais têm propiciado aumento no número de novas estruturas químicas bioativas para inúmeras indicações terapêuticas. Paralelo a esse progresso, desenvolveram-se métodos de screening biológicos automatizados (High Throughput Screening -HTS) que permitem testar in vitro milhares de substân-cias frente a alvos biológicos específicos em curto espaço de tempo.De acordo com Newman, 3 medicamentos derivados de produtos naturais são capazes de tratar 87% das enfermidades humanas categorizadas, incluindo as indicadas como antibacterianas, anticoagulantes, antiparasitárias, imunossupresoras e anticancerígenas. Esta última classe de medicamentos teve 1/3 do mercado em 2002 representado apenas por dois grupos de quimioterápicos derivados de produtos naturais, sendo que os taxanos e derivados da camptotecina representam cerca de U$ 3 bilhões de dólares. 2,5,6A busca por me...

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This study demonstrated that the HTW phenotype was associated with an atherogenic lipid profile, and this phenotype is suggested as a screening tool to identify adolescents with metabolic alterations.

BackgroundThe search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis.MethodsWe prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records.ResultsOf the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis.ConclusionsWe hypothesize that some SCD patients can have a specific dyslipidemic subphenotype characterized by low HDL-C with hypertriglyceridemia and high VLDL-C in association with other biomarkers, including those related to inflammation. This represents an important step toward a more reliable clinical prognosis. Additional studies are warranted to test this hypothesis and the probably mechanisms involved in this complex network of markers and their role in SCD pathogenesis.

It was found that sepsis led to a high oxidative stress and to extensive modification of erythrocytes. It is proposed that a positive feedback mechanism, involving the activation of circulating leukocytes by these modified erythrocytes would maintain the pro-oxidative state even after the disappearance of bacteria.

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