Reproductive organs are essential not only for the life of an individual but also for the survival and development of the species. The response of reproductive organs to toxic substances differs from that of other target organs, and they may serve as an ideal “barometer” for the deleterious effects of environmental pollution on animal and human health. The incidence of infertility, cancers, and associated maladies has increased in the last fifty years or more, while various anthropogenic activities have released into the environment numerous toxic substances, including cadmium, lead, and mercury. Data from epidemiological studies suggested that environmental exposure to cadmium, lead, and mercury may have produced reproductive and developmental toxicity. The present review focused on experimental studies using rats, mice, avian, and rabbits to demonstrate unambiguously effects of cadmium, lead, or mercury on the structure and function of reproductive organs. In addition, relevant human studies are discussed. The experimental studies reviewed have indicated that the testis and ovary are particularly sensitive to cadmium, lead, and mercury because these organs are distinguished by an intense cellular activity, where vital processes of spermatogenesis, oogenesis, and folliculogenesis occur. In ovaries, manifestation of toxicity induced by cadmium, lead, or mercury included decreased follicular growth, occurrence of follicular atresia, degeneration of the corpus luteum, and alterations in cycle. In testes, toxic effects following exposure to cadmium, lead, or mercury included alterations of seminiferous tubules, testicular stroma, and decrease of spermatozoa count, motility and viability, and aberrant spermatozoa morphology.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the invasive growth of epithelial cells via the c-MET oncogene-encoded receptor. In normal lung, both the receptor and the ligand are detected, and the latter is known to be a mitogenic and a motogenic factor for both cultured bronchial epithelial cells and non-small-cell carcinoma lines. Here, ligand and receptor expression was examined in 42 samples of primary human non-small-cell lung carcinoma of different histotype. Each carcinoma sample was compared with adjacent normal lung tissue. The Met/HGF receptor was found to be 2 to 10-fold increased in 25% of carcinoma samples (P = 0.0113). The ligand, HGF/SF, was found to be 10 to 100-fold overexpressed in carcinoma samples (P < 0.0001). Notably, while HGF/SF was occasionally detectable and found exclusively as a single-chain inactive precursor in normal tissues, it was constantly in the biologically-active heterodimeric form in carcinomas. Immunohistochemical staining showed homogeneous expression of both the receptor and the ligand in carcinoma samples, whereas staining was barely detectable in their normal counterparts. These data show that HGF/SF is overexpressed and consistently activated in non-small-cell lung carcinomas and may contribute to the invasive growth of lung cancer.

Introduction: The fluorinated analog of uracil 5-FU is an antimetabolite, active against a wide range of solid tumors. The main mechanism of action consists in interfering with DNA synthesis and mRNA translation. However, patients treated with 5-FU display several side effects, a result of its nonspecific cytotoxicity for tumor cells. Numerous modifications of the 5-FU structure have been performed in order to overcome these disadvantages. Areas covered: In this review, the metabolic pathways, pharmacokinetics and clinical pharmacology of 5-FU are briefly introduced. Moreover, several derivatives developed and patented, including oral 5-FU prodrugs and combinations with other active compounds, are presented. Finally, new innovative methods for administration and vehiculization of 5-FU and its derivatives are described. Expert opinion: The search for less toxic 5-FU derivatives, which diminish or circumvent some of its disadvantages, has allowed the development of selective antitumor prodrugs and novel methods for tissue-specific drug delivery. Although some of these oral prodrugs are being used clinically, either alone or in combination therapy with other anticancer agents, it seems that the potential of personalized medicine, including pharmacogenomics and targeted therapy with novel 5-FU derivatives, will improve the management and clinical responses of patients treated with 5-FU-based therapy.