The purpose of this work is to review the published studies on the mechanisms of action and resistance of 5-fluorouracil. The review is divided into three main sections: mechanisms of anti-tumor action, studies of the resistance to the drug, and procedures for the identification of new genes involved in resistance with microarray techniques. The details of the induction and reversal of the drug resistance are also described.

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Alzheimer’s disease (AD) is characterized by overproduction of β amyloid peptides in the brain with progressive loss of neuronal cells. The 42-aa form of the β amyloid peptide (Aβ42) is implied as a major causative factor, because it is toxic to neurons and elicits inflammatory responses in the brain by activating microglial cells. Despite the overproduction of Aβ42, AD brain tissue also generates protective factor(s) that may antagonize the neurodestructive effect of Aβ42. Humanin is a gene cloned from an apparently normal region of an AD brain and encodes a 24-aa peptide. Both secreted and synthetic Humanin peptides protect neuronal cells from damage by Aβ42, and the effect of Humanin may involve putative cellular receptor(s). To elucidate the molecular identity of such receptor(s), we examined the activity of synthetic Humanin on various cells and found that Humanin induced chemotaxis of mononuclear phagocytes by using a human G protein-coupled formylpeptide receptor-like-1 (FPRL1) and its murine counterpart FPR2. Coincidentally, FPRL1 and FPR2 are also functional receptors used by Aβ42 to chemoattract and activate phagocytic cells. Humanin reduced the aggregation and fibrillary formation by suppressing the effect of Aβ42 on mononuclear phagocytes. In neuroblast cells, Humanin and Aβ42 both activated FPRL1; however, only Aβ42 caused apoptotic death of the cells, and its cytopathic effect was blocked by Humanin. We conclude that Humanin shares human FPRL1 and mouse FPR2 with Aβ42 and suggest that Humanin may exert its neuroprotective effects by competitively inhibiting the access of FPRL1 to Aβ42.

Antiangiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Great progress has been made in developing a "molecular" form of angiogenesis inhibitors; however, the narrow inhibition spectrum limits anticancer efficacy as those inhibitors that usually target a few or even a single angiogenic factor among many angiogenic factors might initially be effective but ultimately lead to the failure of the treatment due to the induction of expression of other angiogenic factors. In this work, we report that with a multiple hydroxyl groups functionalized surface, the Gd@C(82)(OH)(22) fullerenic nanoparticles (f-NPs) are capable of simultaneously downregulating more than 10 angiogenic factors in the mRNA level that is further confirmed at the protein level. After studying this antiangiogenesis activity of the f-NPs by cellular experiment, we further investigated its anticancer efficacy in vivo. A two-week treatment with the f-NPs decreased >40% tumor microvessels density and efficiently lowered the speed of blood supply to tumor tissues by approximately 40%. Efficacy of the treatment using f-NPs in nude mice was comparable to the clinic anticancer drug paclitaxel, while no pronounced side effects were found. These findings indicate that the f-NPs with multiple hydroxyl groups serve as a potent antiangiogenesis inhibitor that can simultaneously target multiple angiogenic factors. We propose that using nanoscale "particulate" itself as a new form of medicine (particulate medicine) may be superior to the traditional "molecular" form of medicine (molecular medicine) in cancer treatment.

The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis.

Copy number alteration (CNA) is a major contributor to genome instability, a hallmark of cancer. Here, we studied genomic alterations in single primary tumor cells and circulating tumor cells (CTCs) from the same patient. Single-nucleotide variants (SNVs) in single cells from both samples occurred sporadically, whereas CNAs among primary tumor cells emerged accumulatively rather than abruptly, converging toward the CNA in CTCs. Focal CNAs affecting the gene and the gene were observed only in a minor portion of primary tumor cells but were present in all CTCs, suggesting a strong selection toward metastasis. Single-cell structural variant (SV) analyses revealed a two-step mechanism, a complex rearrangement followed by gene amplification, for the simultaneous formation of anomalous CNAs in multiple chromosome regions. Integrative CNA analyses of 97 CTCs from 23 patients confirmed the convergence of CNAs and revealed single, concurrent, and mutually exclusive CNAs that could be the driving events in cancer metastasis.

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Pain is one of the hallmarks of inflammation. Opioid receptors mediate antipain responses in both the peripheral nervous system and CNS. In the present study, pretreatment of CCR1:μ-opioid receptor/HEK293 cells with CCL3 (MIP-1α) induced internalization of μ-opioid receptors and severely impaired the μ-opioid receptor-mediated inhibition of cAMP accumulation. Immunohistochemical staining showed that CCR1 and μ-opioid receptors were coexpressed on small to medium diameter neurons in rat dorsal root ganglion. Analysis of ligand-induced calcium flux showed that both types of receptors were functional. Pretreatment of neurons with CCL3 exhibited an impaired [d-Ala2,N-MePhe4,Gly-o15]enkephalin-elicited calcium response, indicative of the heterologous desensitization of μ-opioid receptors. Other chemokines, such as CCL2, CCL5, and CXCL8, exhibited similar inhibitory effects. Our data indicate that proinflammatory chemokines are capable of desensitizing μ-opioid receptors on peripheral sensory neurons, providing a novel potential mechanism for peripheral inflammation-induced hyperalgesia.