Cancer Overview and Antineoplastic Agents

Cancer is a complex disease defined by uncontrolled cell growth, forming malignant tumors that invade surrounding tissues.

Cancer cells multiply at a faster rate than normal cells.

Antineoplastic agents target cancerous cells while minimizing harm to healthy cells.

Alkylating antineoplastic agents attack DNA by attaching an alkyl group to the guanine base. This damages the DNA, preventing cancer cell replication.

Nitrogen mustards are potent chemotherapy agents that belong to the alkylating agent class. They work by attaching an alkyl group to DNA, causing damage and preventing cancer cell replication.

Antibiotics are a class of antineoplastic agents that target specific enzymes involved in DNA synthesis, inhibiting cancer cell growth.

Natural products are derived from various sources like plants, fungi, and bacteria, and can have anticancer properties by targeting specific cellular processes.

Protein Kinase Inhibitors block specific proteins that control cell growth signals, thereby suppressing cancer cell development.

The attachment (R) to the amine nitrogen is the primary determinant of chemical reactivity, oral bioavailability, and side effects.

A key factor in the effectiveness of nitrogen mustards lies in their ability to form a reactive intermediate known as the aziridinium ion. This ion is crucial for alkylating DNA, which ultimately leads to the drug's antineoplastic action.

Aliphatic substituents (attached to non-cyclic carbon chains) donate electrons to the nitrogen, increasing its nucleophilicity and the rate of aziridinium ion formation. This makes the drug more reactive.

Aromatic substituents (like phenyl) withdraw electrons from the nitrogen through resonance, stabilizing the lone pair and slowing down the formation of the aziridinium ion. This lowers reactivity, which can be beneficial for oral administration and reducing side effects.

Triethylenemelamine (Tretamine®) is a triazine derivative with three aziridine rings. It is used against lymphomas and chronic leukemia.

Thiotepa (ThioTEPA) is another aziridine derivative, a phosphoramide that uses parenteral administration to treat breast, ovarian and lung cancers, as well as lymphomas. It gets metabolized into Triethylenphosphoramide (TEPA).

Busulfan, also known as Myleran®, is a butane-1,4-diyl dimethanesulfonate. It acts by alkylating DNA, similar to other alkylating agents. It is primarily used for chronic myelogenous leukemia (CML).

Carmustine, also known as BCNU or BICNU®, is a mustard gas-related nitrosourea, a type of alkylating agent that decomposes in solution to form cytotoxic species, disrupting DNA and proteins.

Organoplatinum anticancer drugs are bifunctional, meaning they can bind to two DNA nucleophiles.

Organoplatinum anticancer drugs are attracted to electron-rich DNA nucleophiles because of their electron-deficient metal atom.

Cisplatin, Carboplatin, and Oxaliplatin are all platinum-based anticancer drugs that work by forming crosslinks between DNA strands.

Cisplatin is the prototype for platinum-based anticancer drugs. It forms crosslinks between guanine bases in DNA, interfering with cell division.

Carboplatin is a more stable derivative of Cisplatin with fewer side effects. It also forms DNA crosslinks.

Oxaliplatin is a third-generation cis-platinum derivative. It is often used in combination with other drugs for colorectal cancer treatment.

Antimetabolites are chemicals that inhibit the use of metabolites, which are essential chemicals in normal metabolism.

Antimetabolites can be harmful to cells because they disrupt normal processes like cell division.

A nitrosourea drug used to treat brain cancers. Its high lipophilicity allows it to cross the blood-brain barrier.

A glucosamine-nitrosourea compound toxic to insulin-producing cells in the pancreas. Used to treat certain pancreatic cancers and induce diabetes in research.

A triazine derivative used to treat various cancers such as melanoma, lymphoma, and sarcoma. It is bioactivated in the liver to form a reactive methanediazonium species.

An imidazotetrazine derivative that produces diazomethane, which alkylates DNA. It is less toxic than its analog, Mitozolomide.

A hydrazine derivative that acts as an alkylating agent through free radical reactions. It is oxidized to azoprocarbazine and produces methylhydrazine, which forms methyl free radicals.

These agents do not directly contain an alkyl group but still damage DNA. They bind to DNA to interfere with repair, acting in a way similar to alkylating agents.

A powerful anti-cancer agent used to treat a wide range of cancers. It inhibits DNA polymerase and is often used in combination with other chemotherapeutic drugs. It can also be used to suppress the immune system.

A key enzyme involved in DNA synthesis and repair. It is inhibited by several anti-cancer drugs, such as methotrexate, which prevent the formation of tetrahydrofolate, a coenzyme necessary for thymidylate synthase activity.

A type of drug that resembles a building block of DNA (pyrimidine) and inhibits the enzyme thymidylate synthase, preventing DNA replication. This disrupts the process that allows cancerous cells to multiply.

A fluorouracil prodrug is a compound that gets converted into an active form within the body. This active form is 5-fluorouracil, a pyrimidine analogue that inhibits DNA replication.

It acts as a suicide inhibitor, causing irreversible damage to the enzyme thymidylate synthase crucial for DNA replication. It prevents cancerous cells from multiplying.

A group of drugs, similar in structure to folic acid, that inhibit the enzyme dihydrofolate reductase (DHFR) in cancerous cells.

Methotrexate is an antifolate drug that blocks the enzyme dihydrofolate reductase (DHFR), interfering with DNA, RNA, and protein synthesis.

A family of antibiotics used in cancer chemotherapy derived from a type of bacteria.

They interrupt DNA and RNA synthesis by inserting themselves between the building blocks of the DNA/RNA chain, preventing cancer cells from copying their genetic material.

Anthracycline antibiotics also block the action of an enzyme called topoisomerase II, which helps untangle DNA. This disruption prevents DNA from being copied properly, halting cancer cell growth.

The E-ring interacts with the enzyme from three positions. The hydroxyl group at position 20 forms a hydrogen bond with Asp533. The lactone forms two hydrogen bonds with Arg364. The D-ring (carbonyl group at position 17) interacts with the +1 cytosine on the non-cleaved strand, stabilizing the topo I-DNA complex.

The configuration of the chiral carbon at position 20 must be (S) for activity. The (R) configuration is inactive.

Topotecan was the first oral topoisomerase I inhibitor approved by the FDA on October 15, 2007.

Topoisomerase II poisons like teniposide increase the levels of the enzyme bound to DNA, preventing DNA replication and translation and leading to apoptosis (programmed cell death).

Catalytic inhibitors of topoisomerase II block the activity of the enzyme, preventing proper DNA unwinding, and hindering DNA synthesis and translation.

Vinca alkaloids, derived from the Madagascar periwinkle, bind to specific sites on tubulin, preventing the assembly of microtubules, which are essential for cell division.

Taxanes, another group of anti-microtubule agents, work by stabilizing microtubules, preventing their disassembly and halting cell division.

Anti-microtubule agents are plant-derived chemicals that interfere with microtubule function, essential for cell division. Two primary groups are vinca alkaloids and taxanes, which have opposite mechanisms of action.