Some General Remarks About Cancer And Cancer Chemotherapy

Cancer is a collective term used for a group of diseases that are characterized by the loss of control of the growth, division, and spread of a group of cells, leading to a primary tumor that invades and destroys adjacent tissues. It may also spread to other regions of the body through a process known as metastasis, which is the cause of 90% of cancer deaths. Cancer remains one of the most difficult diseases to treat and is responsible for about 13% of all deaths worldwide, and this incidence is increasing due to the ageing of population in most countries, but specially in the developed ones.

Cancer is normally caused by abnormalities of the genetic material of the affected cells. Tumorigenesis is a multistep process that involves the accumulation of successive mutations in oncogenes and suppressor genes that deregulates the cell cycle. Tumorigenic events include small-scale changes in DNA sequences, such as point mutations; larger-scale chromosomal aberrations, such as translocations, deletions, and amplifications; and changes that affect the chromatin structure and are associated with dysfunctional epigenetic control, such as aberrant methylation of DNA or acetylation of histones.1 About 2,000-3,000 proteins may have a potential role in the regulation of gene transcription and in the complex

Medicinal Chemistry of Anticancer Drugs © 2008 Elsevier B. V.

DOI: 10.1016/B978-0-444-52824-7.00001-9 All rights reserved.

signal-transduction cascades that regulate the activity of these regulators. Cancer is not only a cell disease, but also a tisular disease in which the normal relationships between epithelial cells and their underlying stromal cells are altered.2

Cancer therapy is based on surgery and radiotherapy, which are, when possible, rather successful regional interventions, and on systemic chemotherapy. Approximately half of cancer patients are not cured by these treatments and may obtain only a prolonged survival or no benefit at all. The aim of most cancer chemotherapeutic drugs currently in clinical use is to kill malignant tumor cells by inhibiting some of the mechanisms implied in cellular division. Accordingly, the antitumor compounds developed through this approach are cytostatic or cytotoxic. However, the knowledge of tumor biology has exploded during the past decades and this may pave the way for more active, targeted anticancer drugs.3 The introduction of the tyrosine kinase inhibitor imatinib as a highly effective drug in chronic myeloid lekemia and gastrointestinal stromal tumors4 was a proof of the concept of effective drug development based on the knowledge of tumor biology.5

Effective targeted therapies may be suitable only for small subgroups of patients.6 Pharmacogenetics, which focuses on intersubject variation in therapeutic drug effects and toxicity depending of polymorphisms, is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. The dose of chemotherapeutic agents is generally adjusted by body surface area, but this parameter is not sufficient to overcome differences in drug disposi-tion.7 DNA microarray technology permits to study alterations in the transcrip-tional level of entire genomes, and may become an important tool for predicting the chemosensitivity of tumors before treatment.

It is obvious that cancer chemotherapy is a very difficult task.8 One of its main associated problems is the nonspecific toxicity of most anticancer drugs due to their biodistribution throughout the body, which requires the administration of a large total dose to achieve high local concentrations in a tumor. Drug targeting aims at preferred drug accumulation in the target cells independently on the method and route of drug administration.9 One approach that allows to improve the selectivity of cytotoxic compounds is the use of prodrugs that are selectively activated in tumor tissues, taking advantage of some unique aspects of tumor physiology, such as selective enzyme expression, hypoxia, and low extracellular pH. More sophisticated tumor-specific delivery techniques allow the selective activation of prodrugs by exogenous enzymes (gene-directed and antibody-directed enzyme prodrug therapy). Furthermore, the increased permeability of vascular endothelium in tumors (enhanced permeability and retention, EPR effect) permits that nanoparticles loaded with an antitumor drug can extravasate and accumulate inside the interstitial space, where the drug can be released as a result of normal carrier degradation (see also Section 4).10

Another problem in cancer chemotherapy is drug resistance. After the development of a resistance mechanism in response to a single drug, cells can display cross-resistance to other structural and mechanistically unrelated drugs, a phenomenon known as multidrug resistance (MDR) in which ATP-dependent transporters have a significant role.11

Finally, a major problem in the development of anticancer drugs is the large gap from promising findings in preclinical in vitro and in vivo models to the results of clinical trials. The problems found in this transition arise because experimental cancer models greatly differ from patients, who very often suffer from a much more complex therapeutic situation. Although a large number of clinical trials are in progress and new results are continuously being published, the real clinical efficacy of most of these treatments is usually disappointing and a statistically significant benefit is observed for very few of them. 2 It has been claimed that development and utilization of more clinically relevant cancer models would represent a major advance for anticancer drug research.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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