Current Cancer Therapy Reviews - Volume 4, Issue 1, 2008

Adoptive cell therapy using cytotoxic CD8+ T lymphocytes (CTL) has shown promising results in recent clinical trials for cancer patients. Although significant advances have been achieved in this field, there are still many issues that need to be addressed before wide application of adoptive cellular immunotherapy as an adjuvant or mainstream therapy for various cancers. Difficulties related to the ex vivo generation of large number of effective antigen-specific CTLs, their in vivo tracking and short term survival following adoptive transfer are among the barriers decelerating the clinical use of this approach. In this review, we focus on recent developments in adoptive cell therapy using CD8 T cells and discuss the hurdles that need to be overcome. In addition, current status of adoptive cell transfer using other T cell populations for cancer immunotherapy that may circumvent some of the problems related to current protocols of using CTL is also discussed.

One of the most important advances in cancer research in recent years is the recognition that killing of tumor cells by anticancer therapies commonly used in the treatment of cancer, e.g. chemotherapy, γ-irradiation, immunotherapy or suicide gene therapy, is predominantly mediated by triggering cell death pathways including apoptosis in cancer cells. Thus, failure to undergo apoptosis may result in treatment resistance of cancers. Understanding the molecular events that regulate apoptosis in response to anticancer therapy and how cancer cells evade apoptotic cell death, provides novel perspectives for a more rational approach to develop molecular targeted therapies for combating cancer.

Purine nucleoside analogues are extensively used in the treatment of malignancies and viral diseases. For example, cladribine and fludarabine are two purine nucleoside analogues that have activity in the treatment of chronic lymphocytic leukemias. These chemotherapeutic agents exert their cytotoxic actions through interactions with intracellular targets. Due to their hydrophilic nature, many purine nucleoside analogues do not readily diffuse across cell membranes at therapeutic concentrations. The presence or absence of mediated transport systems will therefore have an impact on their pharmacological activities. There are two families of nucleoside transporters with members in human (h) cells and tissues: the equilibrative nucleoside transporters (hENTs) and the concentrative nucleoside transporters (hCNTs). These transporter proteins mediate the uptake of both physiologic nucleosides and nucleoside analogue chemotherapeutic agents. It has been documented that permeant specificity, tissue distribution and cellular localization of these transporters contribute to the antineoplastic activity of the purine nucleoside analogues. This article will review current knowledge of the role of nucleoside transport proteins in the cytotoxic actions of purine nucleoside analogues.

KIT and FLT3 are class III trans membrane tyrosine kinases playing key roles in the control of hematopoietic stem cell survival and proliferation. KIT is mutated in about 2.5-3% of acute myeloid leukemia (AML) patients mainly by point mutations occurring at the level of tyrosine kinase domains. FLT3 is mutated in about 30% of AML patients, either by internal tandem duplication of the juxtamembrane domain or by point mutations occurring at the level of tyrosine kinase domains. All these types of mutations lead to the constitutive activation of KIT and FLT3 receptors, respectively. The occurrence of FLT3/ITD mutation is associated with a poor prognosis. These observations have represented the basis for the development of a relatively large number of Tyrosine Kinase Inhibitors (TKI) with activity against KIT and FLT3. The majority of these inhibitors are still in the preclinical phase of study, while few of them have been tested in phase I/II clinical studies. Although these inhibitors when used as single agents have lead to a significant reduction of the number of leukemic blasts, they have produced only transient and limited clinical responses. This efficacy may be related to the occurrence of resistance and to the complexity of the genetic abnormalities occurring in AMLs. The efficacy of FLT3 TKIs in combination with standard anti-leukemic chemotherapeutics has been evaluated in preclinical models and several combination clinical trials are ongoing and have been planned. It is expected that these trials could determine an improvement in the negative prognosis of AML patients with FLT3/ITD mutations. Finally, the combination of FLT3 TKIs with other molecularly targeted agents inhibiting other pathways activated in leukemic cells would determine a major progress in leukemia therapy.

Several decades of investigation concerning the cause and cure of cancer have revealed major discrepancies in the response of different cancer types towards a particular therapy and therefore a need for more effective approaches has been conceived. It is known that cancer development irrespective of its origin occurs due to the compromises that normal cells make in critical pathways, thereby allowing to transform into a tumor. It is thus conceivable that the most effective cancer therapy requires multiple targeting of molecular alterations responsible for malignant transformation. In this context, the development of combinational therapies aimed at multi-cornered attack on cancer cells is of particular significance. The present article is a brief review of the novel trends emerging in cancer therapeutics with special emphasis on epigenetic therapy, cancer stem cell therapy, modern radiotherapy, target based cancer therapy and polyphenol therapy.

Human epidermal growth factor receptor 2 (HER2) is over-expressed in 15%-30% of breast cancers. Women with HER2-positive breast cancer tend to have more aggressive cancer, increased risk of recurrence, and less favorable survival outcomes than women with HER2-negative breast cancer. This review focuses on HER2 and its role in breast cancer pathogenesis. We begin by providing background information on the biological function of HER2 and how this gene contributes to breast cancer development and progression. Next, we review the ongoing debate surrounding the accuracy of available modalities for detecting HER2, namely fluorescence in-situ hybridization (FISH) versus immunohistochemistry (IHC). We include current data examining the relationship between HER2 and possible genetic modifiers, such as topoisomerase IIα, BRCA1, and genomic instability in breast cancer subjects, and how these relationships may influence response to current therapies directed against HER2. We then discuss trastuzumab, a monoclonal antibody used to treat HER2+ breast cancers, and, after providing an overview of the molecular processes involved in targeted therapy, we summarize the current literature regarding outcomes, as well as the potential impact on the overall health of patients, with special attention to cardiac risk involved with such therapy. Finally, we touch on future directions in this field, including newer targeted therapies in development.

Introduction: Cancers are associated with excess cellular oxidative stress, and during cancer treatment the addition of drug-induced oxidative stress can limit the effectiveness of therapy and cause a number of side effects, such as fatigue, nausea, vomiting and diarrhea, as well as more serious adverse effects, including cardiomyopathy, peripheral neuropathy, hepatotoxicity and pulmonary fibrosis. Method: Review of the pertinent literature on oxidative stress during cancer cytotoxic therapy and the use of Molecular Replacement methods to reduce adverse effects by replacement of damaged cellular molecules. Discussion: Most of the adverse effects of cancer therapy are due to oxidative stress-mediated damage to normal tissues. For example, loss of efficiency in the electron transport chain caused by membrane peroxidation and reduction in coenzyme Q10 can occur during cytotoxic therapy using anthracyclines, alkylating agents, platinum coordination complexes, epipodophyllotoxins and camptothecins. Molecular Replacement and antioxidant administration mitigates the damage to normal tissues and reduces the adverse effects of cancer therapy without loss of therapeutic effect. Summary: The acute and chronic adverse effects of cancer chemotherapy can be reduced by Molecular Replacement. Molecular Replacement of membrane lipids and enzymatic cofactors, such as coenzyme Q10, by administering nutritional supplements with antioxidants can prevent oxidative membrane damage and reductions of cofactors in normal tissues, respectively, restoring mitochondrial and other cellular functions and reducing chemotherapy adverse effects, such as cardiotoxicity, without significantly affecting therapeutic benefit. Recent clinical trials using cancer and non-cancer patients with chronic fatigue have shown the benefit of Molecular Replacement Therapy plus antioxidants in reducing the damage to mitochondrial membranes, restoring mitochondrial electron transport function, reducing fatigue and protecting cellular structures and enzymes from oxidative damage.