Potential use of n-3 PUFAs to prevent oxidative stress-derived ototoxicity caused by platinum-based chemotherapy.

Platinum-based compounds are widely used for the treatment of different malignancies due to their high effectiveness. Unfortunately, platinum-based treatment may lead to ototoxicity, an often-irreversible side effect without a known effective treatment and prevention plan. Platinum-based compound-related ototoxicity results mainly from the production of toxic levels of reactive oxygen species (ROS) rather than DNA-adduct formation, which has led to test strategies based on direct ROS scavengers to ameliorate hearing loss. However, favorable clinical results have been associated with several complications, including potential interactions with chemotherapy efficacy. To understand the contribution of the different cytotoxic mechanisms of platinum analogues on malignant cells and auditory cells, the particular susceptibility and response of both kinds of cells to molecules that potentially interfere with these mechanisms, is fundamental to develop innovative strategies to prevent ototoxicity without affecting antineoplastic effects. The n-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) have been tried in different clinical settings, including with cancer patients. Nevertheless, their use to decrease cisplatin-induced ototoxicity has not been explored to date. In this hypothesis paper, we address the mechanisms of platinum compounds-derived ototoxicity, focusing on the differences between the effects of these compounds in neoplastic versus auditory cells. We discuss the basis for a strategic use of n-3 PUFAs to potentially protect auditory cells from platinum-derived injury without affecting neoplastic cells and chemotherapy efficacy.

A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs.

Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively.

Synthesis, characterization, cytotoxic activity, and cellular accumulation of dinuclear platinum complexes derived from N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines, and N-benzyl-1,6-hexanediamines.

This work describes the synthesis and characterization of six new dinuclear platinum complexes having N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines and N-benzyl-1,6-hexanediamines as ligands. They were prepared by the reaction of cis-[PtCl(2)(DMSO)(2)] (DMSO=dimethyl sulfoxide) with the appropriate ligand in water, except for one of them, which was prepared from K(2)PtCl(4). We also report the cytotoxic activity and cellular accumulation of three of these complexes in a human small-cell lung carcinoma cell line and its resistant subline. Resistant cells exhibited a lesser degree of cross-resistance to these compounds when compared to cisplatin. The accumulation of platinum in both cell lines followed the same pattern, i.e. approximately the same intracellular platinum concentration yielded the same cytotoxic effect independent of the nature of the platinum complex used.

Simposio. Avances recientes con ifosfamida/mesna en el tratamiento de tumores sólidos malignos: etopósido, platino, ifosfamida y dexametasona como tratamiento de rescate en los linfomas no Hodgkin / Symposium on recent advances with ifosfamide/Mesna in the treatment of malignant solid tumors

Existen grandes avances en el manejo de los linfomas; desafortunadamente un porcentaje variable de casos recaerán a regímenes de primera línea. Se informan los resultados preliminares de 17 pacientes con diagnóstico de linfoma de Hodgkin refractarios a manejo de primera línea o refractarios. El esquema utilizado fue cada 3-4 semanas: combinación de etopósido 100 mg/m² por tres días, platino 100 mg/m² e ifosfamida 5g/m² fraccionados en tres días, mesna al 20 por ciento de la dosis diaria de ifosfamida por tres dosis; y dexametasona de 20 a 40 mg cada 24 horas por tres días. Trece de los 17 pacientes fueron evaluables para eficacia (dos aún en tratamiento; los otros dos abandonaron la terapia) y 16 fueron evaluables para toxicidad en 74 ciclos administrados. Se obtuvieron 11 respuestas totales (84 por ciento): seis respuestas (46 por ciento) Äcon supervivencia libre de enfermedad mínima de dos meses y máxima de 11 mesesÄ y cinco respuestas parciales (38 por ciento). La toxicidad más frecuente y grave fue neutropenia grado 4 (20 por ciento) con dos muertos por septicemia y plaquetopenia grado 4 (7 por ciento). El resto de los efectos tóxicos fueron leves y reversibles. No se observó toxicidad vasical. Concluimos que el esquema utilizado es efectivo, pero conlleva toxicidad grave en una cuarta parte de los ciclos. Consideramos que es conveniente incluir factores estimulantes de colonias en este tratamiento