Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety, Pharmacovigilance, and Perspectives for Research and Clinical Practice.

The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.

Neonatal Marfan Syndrome.

OBJECTIVE: The Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1) with skeletal, cardiac, and ocular involvement. STUDY DESIGN: We report on a full-term male neonate, who showed at birth characteristics and dysmorphisms suggestive of nMFS, combined with the detection of severe cardiovascular disease. A multidisciplinary team made up of neonatologists and pediatricians, cardiologists, geneticists, ophtalmologists, physiatrists and physioterapists was formed to manage this patient. RESULTS AND CONCLUSION: Early diagnosis of this rare condition is critical for adequate treatment and specific follow-up, and impacts significantly on prognosis.

A centralized Pharmacy Unit for cytotoxic drugs in accordance with Italian legislation.

RATIONALE: In May 2002, a centralized Unit for cytotoxic drug preparations [Unità Farmaci Antiblastici (UFA)] was established at the Centro di Riferimento Oncologico, Aviano, Italy. The Unit was created following provisions under Law 626/94 (Legislative Decree - Ministry of Health), governing the safe handling of cytotoxic drugs. New guidelines governing drug preparation ('NBP' standards of preparation) published in Italian Pharmacopoeia (2002, XI Edition) have been mandatory since 2004 and set out rules for proper pharmacy practice applicable also to antineoplastic drug preparations. Aims and objectives To review legislation on cytotoxic drug preparation and compliance within our Unit, to assess current quality levels and identify those areas requiring improvement. METHODS: The study reviewed: (1) the organization and equipment of the Unit UFA and its working methodology; (2) written documentation concerning work procedures; (3) the stability and sterility of injectable drug formulations; (4) staff training, occupational exposure and risk management; (5) accidents and mistakes occurring in the UFA service. RESULTS: The study showed up the strengths of our Unit and identified those areas which need improvement to guarantee product quality excellence. CONCLUSIONS: A critical evaluation of the whole cytotoxic preparation process is a useful method for quality improvements to be initiated. Knowledge regarding risks, techniques, and procedures for handling antineoplastic drugs is growing. Ongoing analysis will ensure greater patient and health care worker safety.

Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma.

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications.

Radiosensitivity in multidrug-resistant and cisplatin-resistant human carcinoma cell lines.

The radiosensitivity of a multidrug-resistant (MDR) clone and a cisplatin-resistant clone was compared with that of their parental chemosensitive cell lines. The LoVo cell line was derived from a human colon carcinoma, and LoVo-R was the MDR clone. The MDR phenotype is attributable to an increased drug efflux mediated by the P-glycoprotein and involves several classes of structurally unrelated drugs. The 2008 cell line was derived from a human ovary carcinoma and C13 was the cisplatin-resistant clone. Reduced cisplatin accumulation and elevated plasma membrane potential partially account for the drug resistance of C13 cells. The chemoresistance of LoVo-R and C13 cells was confirmed by cytotoxicity tests consisting of 24-hour paclitaxel and 1-hour cisplatin incubation, respectively. The radiosensitivity was evaluated by a clonogenic test. The dose-reducing cell survival fraction from 1 to 0.37 (D(0)), the quasi-threshold dose (Dq), and the survival fraction (SF) after 2 or 4 Gy were determined for each cell line. D(0), Dq, and SF(2) were 1.3 +/- 0.4 Gy, 2.1 +/- 0.6 Gy, and 43 +/- 4% for the LoVo cell line and 1.0 +/- 0.2 Gy, 1.7 +/- 0.4 Gy, and 45 +/- 8%, respectively, for the LoVo-R cell line. D(0), Dq, and SF(4) were 1.7 +/- 0.3 Gy, 3.1 +/- 0.4 Gy, and 43 +/- 12% for 2008 cells and 2.6 +/- 0.5 Gy, 4.3 +/- 0.6 Gy, and 53 +/- 11%, respectively for C13 cells. No significant differences were found between LoVo and LoVo-R cells, whereas C13 cells showed a significantly greater D(0,) Dq, and SF(4) than 2008 cells (p <0.05). Incubation of 2008 and C13 cells with subcytotoxic buthionine (BSO) before and after irradiation partially restored C13 radiosensitivity. In fact, D(0) dropped from 2.8 +/- 0.1 to 2.0 +/- 0.3 Gy in C13 cells with and without BSO, whereas it was 1.9 +/- 0.2 Gy in 2008 cells in the absence and presence of BSO. The total glutathione content (GSH) of C13 cells was 1.5-fold higher than that of 2008 cells. BSO treatment caused a partial depletion of GSH in 2008 and C13 cells, but their radiosensitivity did not change accordingly.

Role of the Multidrug Resistance Protein 1 in protection from heavy metal oxyanions: investigations in vitro and in MRP1-deficient mice.

The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.