RESUMO
Approximately 70% of breast cancers express the estrogen receptor (ER) and endocrine therapy is the most important component of systemic therapy for hormone-responsive breast cancer. Unfortunately, endocrine-resistant ER-positive disease represents up to one-quarter of all breast cancers and a number of different mechanisms have been implicated in endocrine resistance, either intrinsic, occurring de novo at the initial exposure to endocrine therapies or acquired, occurring after an initial response to therapy. In the present work a number of molecular mechanisms accounting for intrinsic and acquired resistance to hormonal therapies have been reviewed and the most promising strategies to overcome endocrine resistance have been highlighted.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Moduladores de Receptor Estrogênico/uso terapêutico , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/metabolismo , Feminino , HumanosRESUMO
Several studies indicate that pain, although very common in the elderly, is under-treated, because it is considered as a concomitant effect of aging. This study aimed to evaluate the prevalence of pain among patients in eight Italian geriatric hospital departments, correlated to prescribed therapy. We enrolled 387 patients in the study, 367 of whom were evaluated. Each patient's recovery, co-morbidity, pain intensity, prescribed therapy, side effects, duration of pain, and efficacy of therapy were monitored during two 15-day periods from 15 July to end of August 2008, and from 1 October to 15 November 2008. The results of this study confirmed that hypertension, cardiopathic disease, diabetes, and chronic obstructive pulmonary disease (COPD) are common pathologies, and that pain is present in 67.3% of those recovered in geriatric departments. In general, however, pain is not treated. Indeed only 49% of those with pain had any type of treatment, which was adequate for the pain intensity. In fact 74.5% of patients considered the therapy to be of low or no efficacy. These data demonstrate the presence of pain in a high percentage of elderly patients, which is either not treated, or treated inadequately. Controlling pain is essential in elderly patients in order to allow a normal life and an active role in family and society. The main conclusion is that pain is often poorly considered in the elderly, thus leading to a dangerous under-treatment. We want to underline the crucial clinical impact of such under-treatment in elderly patients.
Assuntos
Pacientes Internados , Dor/epidemiologia , Idoso , Analgésicos Opioides/uso terapêutico , Comorbidade , Feminino , Avaliação Geriátrica , Humanos , Itália/epidemiologia , Masculino , Dor/prevenção & controle , Medição da Dor , Prevalência , Qualidade de Vida , Fatores de RiscoRESUMO
PURPOSE: To evaluate the antitumor activity of single versus split exposure of neoplastic cells to temozolomide (TZM) and poly(ADP-ribose) polymerase (PARP) inhibitor. METHODS: A leukemic Jurkat cell line and freshly isolated leukemic blasts were used. Jurkat cells are resistant to O6-methylguanine damage induced by TZM due to high levels of O6-alkylguanine-DNA alkyltransferase and to a functional defect in the mismatch repair system. Cells were treated with 3-aminobenzamide or with NU1025 to inhibit PARP activity. TZM was added to cell cultures immediately after PARP inhibitors. The concentrations of TZM used were 62.5 microM (corresponding to the peak plasma concentration in patients) or 125 microM. TREATMENT DESIGN: Cells were treated with 125 microM TZM plus PARP inhibitors (single exposure), or twice with 62.5 microM TZM plus PARP inhibitors with an interval of 24 h between treatments (split exposure). Tumor cell growth, clastogenicity and base excision repair gene transcripts or enzymatic activity were evaluated. RESULTS: The split exposure of Jurkat cells to TZM induced more pronounced and persistent growth inhibition and comparable chromosome damage in comparison with the single exposure. In addition, PARP inhibitors potentiated the cytotoxic effects induced by repeated treatment with TZM in fresh leukemic blasts. A marked decrease in X-ray repair cross-complementing 1 transcript and methylpurine glycosylase (MPG) transcript was detected in Jurkat cells subjected to the split exposure. In this case, a significant reduction in the corresponding enzymatic activity was also observed. CONCLUSIONS: Cytotoxicity induced by TZM and PARP inhibitors can be improved by a fractionated modality of drug treatment. The reduction in MPG transcript and function would presumably contribute to an increase in cell susceptibility to DNA damage induced by the methylating agent and PARP inhibitors.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Aberrações Cromossômicas , Reparo do DNA/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Northern Blotting , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/biossíntese , Regulação para Baixo/efeitos dos fármacos , Citometria de Fluxo , Humanos , Células Jurkat , TemozolomidaRESUMO
Mismatch repair deficiency contributes to tumor cell resistance to O6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO2(CH2)2-lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross-complementing 1 transcript (a component of base excision repair). These results indicate that N3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.
Assuntos
Antineoplásicos/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Mutagênicos/farmacologia , Netropsina/análogos & derivados , Apoptose , Aberrações Cromossômicas , Proteínas de Ligação a DNA/genética , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Células HT29 , Humanos , Células Jurkat , Netropsina/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases , Proteína Supressora de Tumor p53/biossíntese , Proteína 1 Complementadora Cruzada de Reparo de Raio-XRESUMO
In recent years, it has been shown that a nonclassical, major histocompatibility complex-independent system (i.e., CD1-restricted T-cell responses) is involved in T-cell immunity against nonpeptide antigens. The CD1 system appears to function by presenting microbial lipid antigens to specific T cells, and the antigens so far identified include several known constituents of mycobacterial cell walls. Among the four known human CD1 isoforms, the CD1b protein is the best characterized with regard to its antigen-presenting function. Expression of CD1b is upregulated on human blood monocytes upon exposure to granulocyte/macrophage-colony stimulating factor, alone or in combination with interleukin-4 (IL-4) (S. A. Porcelli, Adv. Immunol. 59:1-98, 1995). Rifampin (RFP) and its derivatives are widely used for chemoprophylaxis or chemotherapy against Mycobacterium tuberculosis. However, this agent was found to reduce the mitogen responsiveness of human B and T lymphocytes, chemotaxis, and delayed-type hypersensitivity. The present study extends the immunopharmacological profile of RFP by examining its effects on CD1b expression by human peripheral blood monocytes exposed to GM-CSF plus IL-4. The results showed that clinically attainable concentrations (i.e., 2 or 10 microg/ml for 24 h) of the agent produced a marked increase in CD1b expression on the plasma membrane, as evaluated by fluorescence-activated cell sorter analysis, whereas it had no effect on cytosolic fractions, as indicated by Western blot analysis. This was found to be the result of increased CD1b gene expression, as shown by Northern blot analysis of CD1b mRNA. These results suggest that RFP could be of potential value in augmenting the CD1b-restricted antigen recognition system, thereby enhancing protective cellular immunity to M. tuberculosis.