[Molecular bases of platinum-resistance in testicular cancer]. / Bases moleculares de la resistencia a cisplatino en cáncer de testículo.

Cisplatin has been the cornerstone of germ cell testicular tumors therapy since its introduction more tan 30 years ago, and a basic part of the schemes given to multiple ovarian, lung, head and neck, and bladder tumors among others. Some tumors present primary resistance to this drug, others will develop it despite good initial response. In the case of testicular germ cell tumors most of them are very sensitive to this drug but up to 20% of patients with metastatic disease will present resistance, most of them secondary after a very good initial response. Cisplatin acts by binding to DNA to activate genetic damage recognition mechanisms and apoptosis through the mitochondrial pathway. Resistance mechanisms to cisplatin have been classified in those that happen (1) before its binding to DNA and (2) once it binds to DNA. Most advances in their discovery have used other neoplasias as models, mainly ovarian and lung tumors. In this review we will describe the biological mechanisms behind resistance to cisplatin from the global perspective but trying to focus in testicular germ cell tumors.

Bases moleculares de la resistencia a cisplatino en cáncer de testículo / Molecular basis of platinum-resistance in testicular cáncer

El cisplatino ha sido, desde su introducción hace algo más de 30 años, la piedra angular del tratamiento de los tumores germinales testiculares y parte fundamental en los esquemas administrados en múltiples tumores de origen ovárico, pulmón, cabeza y cuello, vejiga, entre otros. Algunos tumores presentan resistencia primaria a este fármaco, otros la desarrollarán a pesar de una buena respuesta inicial. En el caso de los tumores germinales testiculares la gran mayoría son exquisitamente sensibles a esta droga pero hasta un 20% de los pacientes con enfermedad metastásica presentarán resistencia, la mayor parte secundaria tras una muy buena respuesta inicial. El cisplatino actúa uniéndose al ADN para así activar los mecanismos de reconocimiento de daño genético y activar apoptosis por la vía mitocondrial. Los mecanismos de resistencia a cisplatino han sido clasificados en (1) mecanismos que suceden antes de la unión al ADN, y (2) una vez se ha unido al ADN. La mayoría de los avances en el descubrimiento de los mismos han utilizado como modelos otras neoplasias, mayoritariamente tumores de ovario y pulmón. En esta revisión describiremos los mecanismos biológicos que hay detrás de la resistencia al cisplatino desde la perspectiva global pero intentándonos centrar en los tumores germinales testiculares (AU)

Cisplatin has been the cornerstone of germ cell testicular tumors therapy since its introduction more tan 30 years ago, and a basic part of the schemes given to multiple ovarian, lung, head and neck, and bladder tumors among others. Some tumors present primary resistance to this drug, others will develop it despite good initial response. In the case of testicular germ cell tumors most of them are very sensitive to this drug but up to 20% of patients with metastatic disease will present resistance, most of them secondary after a very good initial response. Cisplatin acts by binding to DNA to activate genetic damage recognition mechanisms and apoptosis through the mitochondrial pathway. Resistance mechanisms to cisplatin have been classified in those that happen (1) before its binding to DNA and (2) once it binds to DNA. Most advances in their discovery have used other neoplasias as models, mainly ovarian and lung tumors. In this review we will describe the biological mechanisms behind resistance to cisplatin from the global perspective but trying to focus in testicular germ cell tumors (AU)

Pre-clinical validation of early molecular markers of sensitivity to aromatase inhibitors in a mouse model of post-menopausal hormone-sensitive breast cancer.

INTRODUCTION: Changes in breast cancer cell biology following hormonal treatment have been claimed as promising predictor markers of clinical benefit even outperforming clinical response. From previous work we selected 10 genes showing both a well known regulation by oestrogen and a high level of early transcriptional regulation following therapy with aromatase inhibitors. Here we use an animal breast cancer model to explore the feasibility of the determination of their expression in minimally invasive samples and to further assess the magnitude of their regulation by letrozole. ANIMAL AND METHODS: Aromatase inhibitor sensitive breast cancer tumours were grown in athymic mice under supplement with androstenedione. Following initial tumour growth animals were assigned to a control group or to receive letrozole at two different dosages. Fine needle aspirates were obtained at the moment of treatment assignation and one week later. Expression of the following genes at both time points was determined: Ki-67, Cyclin D1, pS2, Trefoil Factor 3, PDZ domain containing 1, Ubiquitin-conjugating enzyme E2C, Stanniocalcin 2, Topoisomerase 2 alfa, MAN1A1 and FAS. RESULTS: Fine needles aspirates were found to be a feasible and reproducible technique for RNA extraction. Trefoil Factor 3, pS2, Cyclin D1 and Stanniocalcin 2 were significantly downregulated by letrozole. Among them pS2 appears to be most sensitive to aromatase inhibitor treatment even differentiating sub-optimal from optimal letrozole dosage. DISCUSSION: We present pre-clinical evidence to justify the exploration in clinical trials of pS2, Trefoil factor 3, Cyclin D1 and Stanniocalcin as dynamic markers of oestrogen-driven pathway activation.

Phase II multicentre study of temozolomide in combination with interferon alpha-2b in metastatic malignant melanoma.

OBJECTIVE: Temozolomide is a novel oral alkylating agent, active against metastatic melanoma. Combinations of chemotherapy and biological response modifiers have been associated with increased antitumour activity. A multicentre phase II study was performed to assess the activity and toxicity of temozolomide in combination with interferon alpha-2b. PATIENTS AND METHODS: Eligible patients had histologically confirmed metastatic melanoma. Previously untreated patients received temozolomide administered orally at a dose of 150 mg/m/day for 5 days every 4 weeks, in combination with interferon given continuously subcutaneously twice a week at a dose of 10 MU/m. Treatment continued until disease progression or for a maximum of 12 months. RESULTS: From June 1999 to August 2002, 27 eligible patients were included in the study at six centres. Median age was 59 (28-77) years; 17 male and 10 female patients were recruited; the median Karnofsky performance score was 90 (70-100); three patients had received prior adjuvant interferon; the majority of patients had fewer than three involved sites. A total of 96 cycles were administered; there were one complete response, four partial response and five stable disease (overall response rate: 18.5%, 95% confidence interval: 6.3-38.1). All responses were seen in patients with exclusively lymph node and pulmonary disease [M1a (one patient); M1b (four patients)]. The median response duration was 6.9 months. One patient remains in complete remission at 4 years. The median time to progression and the median survival were 1.87 and 9.5 months, respectively. Haematological toxicity was neutropenia G-IV: 1, G-III: 4, thrombocytopenia G-III: 2, and anaemia G-III: 2. Predominant non-haematological toxicity was hepatotoxicity G-III: 4. Other toxicities were mild or moderate. Dose reduction was required for nine cycles of interferon, one of temozolomide and two of both drugs. CONCLUSIONS: Temozolomide in combination with interferon is a well-tolerated palliative regimen that has moderate activity against metastatic melanoma. Further evaluation of this regimen in comparative studies or in combination with other drugs is warranted.

A phase I clinical and pharmacokinetic study of paclitaxel and docetaxel given in combination in patients with solid tumours.

The aim of this study was to determine the safety and feasibility profile of paclitaxel (PTX) and docetaxel (DTX) in combination and the pharmacokinetic and pharmacodynamic interaction between these two drugs in two different alternated sequences of administration. The starting dose was PTX (100 mg/m(2)) as a 3-h IV infusion followed by DTX (50 mg/m(2)) as 1-h IV infusion or the alternative sequence in every other patient. The sequence was alternated in the second course in each patient treated. Cycle duration was 21 days. Twenty patients received 103 cycles of treatment through three dose levels. Febrile neutropenia and grade 4 neutropenia lasting longer than 7 days were dose-limiting and defined the toxic dose of DTX (50 mg/m(2)) and PTX (135 mg/m(2)) in patients with prior treatment and the recommended dose in patients without prior treatment. Non-hematological toxicities included asthenia, neuropathy, arthralgia/myalgia and stomatitis. Pharmacokinetics of DTX were significantly affected by the sequence. Nadir ANC was more profound when DTX was administered first (P=0.022). There were one complete response and six partial responses, giving an overall response rate of 35%. DTX (50 mg/m(2)) followed by PTX (135 mg/m(2)) can be administered safely and it is an active regimen. The pharmacokinetics of PTX are not influenced by DTX but DTX pharmacokinetics depend on the sequence of administration, which influences its haematological toxicity profile.

Evaluación de los proyectos de investigación clínica en un centro monográfico de cáncer / Evaluation of clinical research studies in a comprehensive cancer center

FUNDAMENTO Y OBJETIVO: La investigación mediante ensayos clínicos en el tratamiento del cáncer ha ido en progresivo aumento en los últimos años. Existen pocos datos que evalúen la magnitud y el impacto de esta actividad investigadora en centros hospitalarios en nuestro ámbito territorial. El objetivo de este artículo es conocer y evaluar la actividad investigadora clínica de un centro oncológico durante 7 años. MATERIAL Y MÉTODOS: Se realiza un análisis descriptivo de los siguientes parámetros registrados: selección de protocolos, índice de aceptación, origen de propuestas, promotores e investigadores; datos de los estudios realizados, fase, cumplimiento y su publicación en revistas biomédicas. Los datos recogidos de pacientes son demográficos y de inclusión en los diferentes tipos de estudios. RESULTADOS: Se han evaluado 337 propuestas de ensayo clínico entre 1996 y 2002 siguiendo un sistema estandarizado de revisión, con un descenso del índice de aceptación de protocolos del 62,5 por ciento en 1996 al 39,2 por ciento en 2002, mientras que el número de protocolos ha pasado de 16 a 72 anuales. El índice general de reclutamiento de pacientes en la institución es del 6,64 por ciento respecto al número de primeras visitas. Se han registrado 1.479 pacientes (19962002), sólo un 5 por ciento mayores de 75 años. La industria farmacéutica promueve la mayoría de los ensayos clínicos, aunque el papel de los grupos cooperativos es predominante en disciplinas como la hematología clínica y la oncología radioterápica. De 23 estudios iniciados entre 19961998 y finalizados, se han publicado 13 y hay 3 en vías de publicación (69,5 por ciento). CONCLUSIONES: El porcentaje de inclusión de pacientes en ensayos clínicos es limitado. Ello representa a un porcentaje reducido de la población global de pacientes que acuden a un centro monográfico de cáncer, y están siendo especialmente mal representados los mayores de 75 años (AU)