Antineoplastics

Introduction
The antineoplastic drugs are designed to either inhibit abnormal cell proliferation or to cause  death of abnormal cells.  Given the complex biochemical pathways and the specific phases of cellular life cycles, there are numerous opportunities for these drugs to exert a beneficial effect.

Summarising the biochemical requirements for successful cell life and division, bases (purines and pyrimidines) that ultimately form RNA and DNA must first be synthesised (antimetabolites may inhibit this step).  Upon synthesis, these bases are used to form ribonucleotides, which are then reduced to form deoxyribonucleotides (this step may be inhibited by hydroxyurea) and used to form DNA (many of the steps from ribonucleotide reduction through DNA synthesis may be inhibited by antimetabolites or folate antagonists).  (DNA structure and function may be inhibited at any point during the life of a cell by agents such as the alkylators and the anthracycline antibiotics.)  The DNA is then used as a template to form RNA, which is used to synthesis proteins (DNA function may be inhibited here OR protein synthesis may be inhibited by L-asparaginase) that may be required for cell life or division (such as microtubules, whose function may be inhibited by the antimitotic antineoplastics).  Additionally, at cell division, the DNA is replicated for daughter cells (this may be inhibited as well).  The entire scheme is illustrated below:

One aspect of neoplastic cells is a high proclivity to replication.  Considering the cell cycle, recall that there are four distinct phases in the life of a cell.  The G1 phase is a pre-DNA synthesis phase during which purines are synthesised and ribonucleotides are formed.  As the necessary components for DNA synthesis are accumulated, the cell enters the S phase, during which DNA synthesis occurs.  Following DNA synthesis, the cell prepares to divide during the pre-mitotic G2 phase.  Once the cell has prepared itself, it enters the M or mitotic phase, in which the four stages of mitosis (prophase, metaphase, anaphase, and telophase) occur.  Some cells also exhibit a G0 or resting phase that may proceed the G1 phase.  Depending upon their mechanism of action, antineoplastics may exert their effect specifically during one of these phases -- these are called cell-cycle specific antineoplastics and are illustrated below.  Conversely, other drugs may act during any phase of the cell cycle to cause cell death -- these are termed non-cell cycle specific antineoplastics.  As damage occurs to the cell one of two actions may take place.  Damage to DNA may prevent replication by altering DNA, RNA or their function.  Agents which work by this mechanism inhibit the proliferation of the neoplastic cell (it cannot divide).  Other drugs may cause damage to the DNA that results in cell death.  This action has been correlated to the presence of a specific gene, the p53 gene.  If DNA damage occurs and the p53 gene is present, then as the cell proceeds from the G1 phase to the S phase, the damage is detected and results in cell death by apoptosis.  Apoptosis has been referred to as programmed cell death and may represent the natural "life limit" of the cell.  Absence of the p53 gene will prevent cell death or allow the cell to survive (this is one mechanism of resistance that may develop to anti-neoplastics).  The ability of most antineoplastics to damage DNA will cause cell death by this mechanism, accounting for their cytotoxic effects.

Antineoplastic Agents
The primary goal of these drugs, as stated above, is to kill or inhibit proliferation of abnormal cells.  This is best accomplished by administering the highest dose possible (one that does not endanger the life of the patient).  Since these agents may present with severe toxicity, there are several agents whose dose may be limited by their toxicity.  Since many of these agents act by different mechanisms, combination therapy is common.  Additionally, since these drugs act by inhibiting cell division, the most common side effects are those that occur in areas of the body where cell replication occurs, such as the GI mucosa (nausea, vomiting, diarrhœa), the bone marrow (myelosuppression causing leukopænia and other blood dyscrasias), and hair follicles (alopecia).  Most antineoplastics have less effects on those cells that are non-dividing (kidney, heart) and effects on these organs are often the result of damage to portions of the cell other that DNA.  These side effects (except alopecia) may represent the dose limiting toxicity (DLT) or some other toxic effect may limit the dose of a particular anti-neoplastic.
Antineoplastics, while sharing many of the same mechanisms of action, may exhibit varying degrees of efficacy in different neoplasias.  This may represent differences in the growth cycle of the specific neoplasia or it can result from different uptake mechanisms, that may limit the amount of drug that reaches the nucleus of the neoplastic cell.  Antineoplastic drugs enter the cell by different mechanisms including active transport (often at sites for amino acids or other cell constituents such as choline) and passive diffusion.  Changes in the uptake of the drug represent one form of resistance that may develop to antineoplastic therapy.  Other forms of resistance include increases in glutathione production, which may serve as the site of drug action, reducing its effect on DNA, increased efficiency in DNA repair, increased metabolism of the drug, and failure to express the p53 gene as previously described.
 

Alkylating Agents

Antimetabolites Natural Products Miscellaneous Antineoplastics Other Antineoplastics Go To Next Topic -- Miscellaneous Drugs That Treat Miscellaneous Proliferative Disorders