Basic Principles Underlying The Development Of Combination Therapy

Cancer is the name given to a collection of abnormal cells growth many diseases. In all types of cancer, some of the body s cells begin to divide without stopping and spread into surrounding tissues.

Cancerous tumors are malignant, which means they can spread into, or invade, nearby tissues. In addition, as these tumors grow, some cancer cells can break off and travel to distant places in the body through the blood or the lymph system and form new tumors far from the original tumor.

Cancer cells differ from normal cells in many ways that allow them to grow out of control and become invasive. One important difference is that cancer cells are less specialized than normal cells. That is, whereas normal cells mature into very distinct cell types with specific functions, cancer cells do not. This is one reason that, unlike normal cells, cancer cells continue to divide without stopping.

Cancer is a genetic disease that is, it is caused by changes to genes that control the way our cell s function, especially how they grow and divide. Genetic alterations probably represent the most common mechanisms for molecular changes that cause the development and progression of cancer.

Great efforts have been made to identify common genetic modifications and the underlying target genes. Genetic alterations can be inherited, as in hereditary cancers, or induced by endogenous and exogenous carcinogenic factors as in most sporadic cancers.

Types of cancer are usually named for the organs or tissues where the cancers form. For example, lung cancer starts in cells of the lung, and brain cancer starts in cells of the brain. Cancers also may be described by the type of cell that formed them, such as an epithelial cell or a squamous cell.

Chemotherapeutic agents used in current clinical practice have played a significant role in reducing mortality/morbidity and in increasing patient s quality of life. Despite the recent advances in early diagnosis and in clinical protocols for cancer treatment, the development of antineoplastic agents that combine efficacy, safety and convenience for the patient remains a great challenge.

Combination therapy has been the standard of care, especially in cancer treatment, since it is a rationale strategy to increase response and tolerability and to decrease resistance.

The fundamentals of combination chemotherapy development have remained largely unchanged over the last decades. The general principles have been to:

i) use drugs with nonoverlapping toxicities so that each drug can be administered at near-maximal dose

ii) combine agents with different mechanisms of action and minimal cross-resistance in order to inhibit the emergence of broad-spectrum drug resistance

iii) preferentially use drugs with proven activity as single drugs and iv) administer the combination at early-stage disease and at a schedule with a minimal treatment-free period between cycles but still allowing the recovery of sensitive target tissues.

The advantages attributed to combination chemotherapy include

improved patient compliance due to the reduced number of administrations,

emergence of additive or synergistic interaction effects,

ability to overcome or delay MDR and reduction of drug dose with consequent diminishing of toxicity to healthy tissues.

Examples

The alkylating agents impair cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules. The most important sites of alkylation are DNA, RNA, and proteins. The electron-rich nitrogen at the 7 position of guanine in DNA is par ticularly susceptible to alkylation.

Cisplatin is an inorganic heavy metal complex that has activity typical of a cell-cycle-phase nonspecific alkylating agent. The compound produces intrastrand and interstrand DNA cross-links and forms DNA adducts, thereby inhibiting the synthesis of DNA, RNA, and proteins. Carboplatin has the same active diamine platinum moiety as cisplatin, but it is bonded to an organic carboxylate group that allows increased water solubility and slower hydrolysis to the alkylating aqueous platinum complex, thus altering toxicity profiles. Oxaliplatin (Eloxatin) is distinguished from the other platinum compounds by a di-amino-cyclohexane ring bound to the platinum molecule, which interferes with resistance mechanisms to the drug.

Antimetabolites are structural analogs of the naturally occurring metabolites involved in DNA and RNA synthesis. As the constituents of these metabolic pathways have been elucidated, a large number of structurally similar drugs that alter the critical pathways of nucleotide synthesis have been developed

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