Current Cancer Therapy Reviews - Volume 2, Issue 2, 2006

HTLV-1 is etiologically implicated with adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). Neither of them is curable by presently known therapy. Therefore, both disorders are waiting for novel therapeutic approaches. Developing such approaches requires comprehensive insight into the viral and cellular factors involved in the genesis of these diseases. It is widely accepted that the viral Tax protein plays a key role in initiating the process leading to ATL, as well as in the pathogenesis of TSP/HAM. Therefore, its various activities are attractive targets for novel molecular or/and immunological therapies. This review describes the effects of Tax that confer its oncogenic potential. These effects require a sufficiently high level of Tax protein, whereas shortly after human infection, the virus enters into a latent state in which no or very low viral gene expression and Tax protein can be detected in the infected cells of the virus carriers. This implies that the dormant virus must be activated in order to elevate Tax protein to its effective level. We review here our and others' data suggesting that this activation can be triggered by stressinducing environmental agents and discuss the mechanism of this activation. In addition, we discuss the pathogenic progression following this virus activation and finally we present perspectives for molecular therapeutic approach for HTLV-1 related clinical disorders.

Resistance of tumor cells to chemotherapeutic agents and to radiation is one of the major obstacles in the treatment of human cancers. The exact mechanism by which cells develop resistance to chemotherapeutic and radiotherapeutic agents is not well understood. Accumulating evidences over the last decade suggests however that transcription factor nuclear factor-kappa B (NF-κ B) may play an important role in both chemoresistance and radioresistance. Three lines of evidence support this position. First, most chemotherapeutic agents and gamma radiation activate NF-κ B in vitro and in vivo. Second, induction of chemoresistance and radioresistance is mediated via genes regulated by NF-κ B. Third, inhibition of NF-κ B and NF-κ B-regulated gene products increases sensitivity of cancer cells to apoptotic action of chemotherapeutic agents and to radiation exposure. This review focuses on current knowledge of the regulation of resistance of tumors cells to chemotherapeutic agents and gamma radiation by NF-κ B and the therapeutic potential of targeting NF-κ B in cancer treatment.

Modification of chromatin without actually altering its nucleotide sequence is termed epigenetic modification. These modifications include changes in methylation, acetylation and phosphorylation levels of histones as well as methylation of CpG islands in DNA. Besides these covalent modifications, ATP-dependent alterations of chromatin topology also represent another level of chromatin remodeling. All these changes eventually affect expression of various proteins. Condensation of chromatin structure to a heterochromatin form leads to silencing of genes whereas decondensation to euchromatin structures is associated with de-repression. In general, acetylation of lysine residues in histones leads to increased expression while methylation of these residues results in silencing. Methylation of CpG islands can also lead to gene silencing. Since cancer is associated with aberrant expression of various genes caused by epigenetic alteration that are essentially reversible, targeting epigenetic modifications may serve as a useful tool to design strategies for cancer therapy. In the past few years, serious efforts were bestowed to explore this possibility and different pathways are being tested for their usefulness as anti-cancer targets. These targets include the cell cycle, apoptosis and angiogenesis regulatory genes. Another interesting epigenetic approach under investigation is to induce senescence in tumor cells. This is based on the theory that senescence is a potential tumor suppressor mechanism. In this review we summarize recent findings aimed towards exploiting epigenetic modification as potent cancer therapeutic strategies with special emphasis on cell cycle, senescence, apoptosis and angiogenesis related genes.

There is a wide variation in cancer incidence in humans, which, in part, has been attributed to metabolic factors of carcinogens and genetic polymorphisms in drug metabolising enzymes and drug transporters. Drug metabolising enzymes are responsible for the initial activation of many (pro)carcinogens, such as polycyclic aromatic hydrocarbons (PAH), to biologically reactive metabolites. Besides, detoxifying enzymes are responsible for the inactivation of these active carcinogens and deficiency of these enzymes may result in an increase of cancer risk in exposed individuals. Another factor influencing interindividual variability in cancer incidence is the transporters, which are responsible for the excretion of carcinogens. A high number of polymorphisms have been described in drug metabolising enzymes and drug transporter genes. These polymorphisms might influence the activity of metabolising enzymes and drug transporters and thereby affect cancer risk. This review will focus on the role of genetic polymorphisms of selected drug metabolising enzymes (CYP1A1, 2C9, 2C19, 3A4, 3A5, UGT1A1, GSTM1, GSTP1, GSTT1, SULT1A1, NAT1 and NAT2) and ABCtransporters (P-gp and BRCP) in relation to cancer risk.

The insulin-like growth factor (IGF) system involves a complex network of ligands (IGF-I and IGF-II), receptors (IGF-1R and IGF-2R), IGF-binding proteins (IGFBP-1 to IGFBP-6), and downstream intracellular signaling elements. The IGF-axis modulates proliferation and (anti-)apoptosis in mammals, and it is therefore not surprising that dysregulation of different pathway components is involved in the development and progression of several tumor entities such as breast, prostate, lung, and liver cancer. Because IGFs, IGF-receptors, and IGFBPs play a critical role in the emergence of human neoplasias, these molecules have become the center of special interest as prime targets for potential anti-cancer therapies. In the last decade, various substances and experimental strategies, which affect the IGF-induced signal transduction, have successfully been used in treatment of neoplasias in vitro and in vivo. These approaches contain neutralizing antibodies, antagonistic peptides, selective receptor kinase inhibitors, and (antisense-)oligonucleotides.

Melphalan in combination with glucocorticoid steroids has been an important first-line treatment option for multiple myeloma (MM) for over 40 years, but response rates have been only 50-60%, with less than 5% complete remissions (CRs). More intensive combinations of chemotherapy such as vincristine, Adriamycin and Dexamethasone (Dex) (VAD) improved objective response rates to 40%-70%, with 10-17% complete responses, but overall survival (OS) was not significantly improved. High-dose therapy with autologous hematopoietic stem cell transplantation (AHCT) has improved OS by approximately 12 months in three prospective randomized trials, but is not available to many patients. More recently, novel therapies thalidomide, the immunomodulatory thalidomide analogue Revlimid, and the proteasome inhibitor bortezomib have demonstrated significant activity to overcome drug resistance in patients with relapsed and refractory MM. Early results indicate that these novel therapeutics have even more impressive activity in combination with conventional therapies prior to AHCT, as well as following AHCT. Furthermore, these novel therapies should be more widely available to most patients with MM.

Cancer costs the life of over 6 M human beings from around the world every year. More than 1.3 million new cases are predicted to be diagnosed only in the USA during 2005 with over 570,000 deaths estimated. A better understanding of the molecular basis of carcinogenesis has facilitated progress towards improving early detection and prevention as well as the development of more efficient and specific treatments against certain types of cancer. However, very few successful anticancer agents exist today and aggressive tumors are still incurable. Retinoids are natural and synthetic derivatives of vitamin A, which have shown promise for the prevention and treatment of cancer because of their cell growth inhibition and differentiation activities. Unfortunately, their clinical use has been stalled by significant toxicity caused by the broad biological responses mediated by the nuclear retinoid receptors. Synthetic retinoid-related molecules containing an adamantyl group have been shown to induce apoptosis and show promising anticancer activity in animal models, therefore representing optimal leads for the development of novel retinoid-like anticancer drugs. These compounds induce apoptosis via the mithochondrial pathway and seem to function independently of nuclear retinoid receptor activity. In contrast, they have an effect on various cytosolic signaling pathways, including activation of stress kinases (cJun N-terminal kinase and p38 kinase) and inhibition of survival kinases (I κB kinase).