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Aitziber Buqué,,
Unai Aresti,,
Begoña,,
Jangi Sh Muhialdin,, Alberto Muñoz,,
Sergio Carrera,,
Eider Azkona,,
Itziar Rubio,,
Guillermo López-Vivanco
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ABSTRACT: Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.
PLoS ONE 05/2013; 8((5)):e63338. · 4.09 Impact Factor
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ABSTRACT: BACKGROUND: Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. It represents a challenge for oncologist, as the current treatment options are non-curative in the majority of cases; therefore, the effort to find and/or develop novel compounds is mandatory. Pemetrexed (Alimta(R), MTA) is a multitarget antifolate that inhibits folate-dependent enzymes: thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, required for de novo synthesis of nucleotides for DNA replication. It is currently used in the treatment of mesothelioma and non-small cell lung cancer (NSCLC), and has shown clinical activity in other tumors such as breast, colorectal, bladder, cervical, gastric and pancreatic cancer. However, its effect in human melanoma has not been studied yet. RESULTS: In the current work we studied the effect of MTA on four human melanoma cell lines A375, Hs294T, HT144 and MeWo and in two NSCLC cell lines H1299 and Calu-3. We have found that MTA induces DNA damage, S-phase cell cycle arrest, and caspase- dependent and - independent apoptosis. We show that an increment of the intracellular reactive oxygen species (ROS) and p53 is required for MTA-induced cytotoxicity by utilizing N-Acetyl-LCysteine (NAC) to blockage of ROS and p53-defective H1299 NSCLC cell line. Pretreatment of melanoma cells with NAC significantly decreased the DNA damage, p53 upregulation and cytotoxic effect of MTA. MTA was able to induce p53 expression leading to up-regulation of p53-dependent genes Mcl-1 and PIDD, followed by a postranscriptional regulation of Mcl-1 improving apoptosis. CONCLUSIONS: We found that MTA induced DNA damage and mitochondrial-mediated apoptosis in human melanoma cells in vitro and that the associated apoptosis was both caspase-dependent and - independent and p53-mediated. Our data suggest that MTA may be of therapeutic relevance for the future treatment of human malignant melanoma.
Molecular Cancer 04/2012; 11(1):25. · 3.99 Impact Factor
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Clinical and Translational Oncology 12/2007; 10(1):64-65. · 1.33 Impact Factor
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Acta Oncologica 02/2007; 46(3):397-9. · 3.33 Impact Factor
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ABSTRACT: Metastatic non-small-cell lung cancer is a common condition with a dismal prognosis. Although palliative chemotherapy improves survival and quality of life, nearly all patients die of progressive disease. Metastatic involvement of adrenal glands is not rare, but usually reflects widespread dissemination. Selected patients with single adrenal metastasis may be cured with surgery, although the level of evidence comes from single cases reports and short retrospective series. Here we report a patient with bilateral adrenal metastases from previously resected non-small-cell lung cancer, who remains free of disease four years after pre-operative chemotherapy and bilateral adrenalectomy.
Japanese Journal of Clinical Oncology 12/2006; 36(11):731-4. · 1.78 Impact Factor
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Journal of the American Academy of Dermatology 03/2006; 54(2 Suppl):S50-2. · 3.99 Impact Factor
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New England Journal of Medicine 02/2006; 354(3):305-7; author reply 305-7. · 53.30 Impact Factor
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Acta Oncologica 02/2006; 45(5):621-2. · 3.33 Impact Factor
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Archives of Dermatology 11/2005; 141(10):1326-7. · 3.89 Impact Factor
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ABSTRACT: In an attempt to increase the dose intensity of cisplatin and gemcitabine given to patients with stage IIIB or IV nonsmall cell lung cancer without increasing toxicity, we have studied a biweekly administration schedule. We analyze the safety and efficacy of this treatment.
In this study, cycles of 50 mg/m2 cisplatin with 2500 mg/m2 gemcitabine were given on days 1 and 15 every 28 days. The median age of the 49 patients was 62 years and 23 were in stage IIIB patients (46.9%), whereas 26 (53.1%) were in stage IV.
Overall response rate was 38.8%, 52.2% for stage IIIB and 26.9% for stage IV. Median survival was 48 weeks and 1-year survival was 44%, with 66.7% of stage IIIB patients and 13.3% of stage IV patients surviving for 1 year. In the study, 178 cycles were administered, a mean of 4 cycles per patient. The intensity of the 359 administrations reached 91.16% of the planned dosage, although 49 were delayed for 1 week while subjects recovered from the toxicity. There was 1 toxic death and 2 patients experienced vascular toxicity with distal arterial ischemic severe changes in their lower extremities. There were 7 episodes of grade 2 neutropenia, 2 of grade 3, and one of grade 4; however, no cases of febrile neutropenia were seen. The predominant nonhematologic toxic effects were asthenia and nausea/vomiting.
The schedule of cisplatin and gemcitabine analyzed is active with a good therapeutic index.
American journal of clinical oncology 11/2005; 28(5):501-7. · 2.21 Impact Factor
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Journal of Clinical Oncology 10/2005; 23(27):6797-8; author reply 6798-9. · 18.37 Impact Factor
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Cancer 10/2005; 104(5):1110-1; author reply 1111. · 4.77 Impact Factor
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Journal of the American Academy of Dermatology 05/2005; 52(4):711-2. · 3.99 Impact Factor
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Cancer 09/2004; 101(3):653-4; author reply 654-5. · 4.77 Impact Factor
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ABSTRACT: Taxane-based combinations appear to be promising for the treatment of carcinoma of unknown primary site (CUPS).
Patients with CUPS not corresponding to any favourable subset were treated with paclitaxel, carboplatin and etoposide. Interaction between various factors with survival was analyzed. A regression model was applied to identify factors with independent prognostic significance.
48 patients were included and 15 responses were observed with a median overall survival of 7.4 months. In the multivariate analysis, performance status and hypoalbuminemia were negatively associated with overall survival.
Some patients can achieve complete response and prolonged survival. This treatment cannot be recommended for patients with a regular performance status. A better knowledge of prognostic factors and a definition of more subgroups with favourable outcome are needed.
Medicina Clínica 03/2004; 122(6):216-8. · 1.38 Impact Factor
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New England Journal of Medicine 01/2004; 349(23):2272-3; author reply 2272-3. · 53.30 Impact Factor
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CancerSpectrum Knowledge Environment 09/2003; 95(16):1252-3. · 14.07 Impact Factor
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ABSTRACT: Clinical systemic amyloidosis has been rarely described in patients with lung cancer. A new case of such an association is described with a review of the literature and a discussion about the possible biological mechanisms responsible for the development of systemic amyloidosis in patients with lung cancer. Circulating precursors of amyloid fibrils in patients with lung cancer might be implicated more than expected in the biology of tumoral disease.
Clinical Lung Cancer 02/2003; 4(4):249-51; discussion 252. · 2.94 Impact Factor
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ABSTRACT: The aim of this phase II trial was to assess the efficacy and tolerability of docetaxel/vinorelbine as second-line therapy. Thirty-two patients with a performance status (PS) of <or= 2 (5 with locally advanced and 27 with metastatic non-small-cell lung cancer [NSCLC]) who were previously treated with platinum-based chemotherapy, were recruited. Docetaxel 75 mg/m2 on day 1 and vinorelbine 20 mg/m2 on days 1 and 5 were administered every 3 weeks with dexamethasone premedication but without prophylactic granulocyte colony-stimulating factor and antibiotics. The overall response rate (intent-to-treat analysis) was 9.5%, including 3 patients with a partial response, 15 (47%) with stable disease, and 9 (28%) with progressive disease. Myelosupression was the limiting toxicity, with 8 episodes of febrile neutropenia and 3 deaths due to sepsis. Median overall survival and progression-free survival were 25 weeks and 13 weeks, respectively. Patients with a PS of 2 (P < 0.02) and elevated lactate dehydrogenase (P < 0.01) had a worse prognosis. Histology of adenocarcinoma appeared to positively influence survival (P = 0.09). Our study confirms that the docetaxel/vinorelbine schedule has activity in NSCLC patients pretreated with platinum-based therapies.
Clinical Lung Cancer 12/2002; 4(3):168-73. · 2.94 Impact Factor
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ABSTRACT: The objective of the study was to evaluate the efficacy of combined chemoradiation in patients with newly diagnosed glioblastoma multiforme. The main end points were time to progression and overall survival.
Thirty-one patients with glioblastoma multiforme underwent surgery whenever possible and then received intravenous VM26 (120 mg/m2) and oral CCNU (120 mg/m2) for three cycles followed by radiotherapy (60 Gy).
Surgery consisted of a complete resection in 39% of patients, partial resection in 35% and a biopsy in 26%. Sixteen patients had clinical or radiological evidence of progression during or after chemotherapy. Hematologic toxicity was mild. Forty-five percent of patients received the scheduled dose of radiation. The outcome was disappointing, with a median time to progression of 18 weeks and median survival of 37.17 weeks.
The survival of patients with glioblastoma multiforme remains disappointing. Multimodal therapy does not seem to modify the evolution of the tumor. Stratification according to prognostic factors might detect a potential benefit of other therapeutic approaches.
Tumori 90(6):562-6. · 0.86 Impact Factor
