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Medical Pharmacology Topics   

Preliminary Outline

Alkylating Agents
  Monofunctional
       Dacarbazine
       Streptozotocin
       Procarbacine
  Nitrogen Mustards
       Nitrogen Mustard
       Chlorambucil
       Cyclophosphamide
       Melphalan
  Alkyl Sulfonates
       Busulfan
   Chloroethylnitrosoureas
       BCNU
       CCNU
       MeCCNU
       Chlorozotocin
  Other
       AZQ
Platinum Agents
       Cisplatin
       Carboplatin

Adduct-Forming Agents

The adduct-forming agents include the alkylating agents and platinum compounds.The alkylating agents damage DNA by adding alkyl adducts to DNA bases, at either one or two sites per drug molecule. The platinum compounds form similar adducts.

Monofunctional Alkylating Agents

The monofunctional alkylating agents alkylate at a single DNA site, and include dacarbazine, streptozotocin and procarbazine. They are used to treat Hodgkin's and other lymphomas.

Dacarbazine requires activation in the liver, although the active metabolite is unknown. It inhibits DNA, RNA and protein synthesis, probably by methylation of DNA at N7 or O6 of guanine.

Streptozocine does not require metabolic activation, and 7% of its methylation of DNA occur at guanine O6. It is used primarily to treat pancreatic islet cell carcinoma, and will induce diabetes in experimental rats.

Procarbazine requires activation by cytochrome P450, and the postulated final active metabolite is a diazomethane. Its most common use is in Hogdkin's lymphoma, in the MOPP therapy.

Nitrogen Mustrads

The general mechanism of action of the nitrogen mustards is the formation of ethylene ammonium ions capable of forming a covalent bond with macromolecules. These ions form crosslinks between complementary strands of DNA and between DNA and protein, and induce alkylation of proteins.

The chloride ion is not displaced in plasma because the chloride concentration is relatively high. But once inside the cell, the chloride concentration is low and the Cl dissociates forming the ethylene ammonium. Alkylated bases may undergo a ring opening step which is subsequently repaired.

The nitrogen mustards include nitrogen mustard, chlorambucil, cyclophosphamide and melphalam. Nitrogen mustard acts mostly by forming DNA inter- and intrastrand crosslinks and DNA-protein crosslinks. The primary site of alkylation is the guanine N7 position, and the N7 position of an adjacent guanine or adenine. In vitro, peak DNA damage by nitrogen mustard occurs within the first hour, and lesions are repaired in 12-24 hours.

The primary use of nitrogen mustard is the treatment of Hodgkin's lymphoma in the MOPP regime. It is very reactive in aqueous solution and free drug cannot be detected in plasma after a few minutes of IV infusion. The main side effects are menstrual irregularities in females and sterility in males.

Chlorambucil is the drug of choice for the treatment of chronic lymphocytic leukemia, as well as lymphomas. A cyclohexyl ring provides increased stability that allows oral administration. The plasma half life is 1 hour.

Cyclophosphamide is one of the most stable nitrogen mustards, and requires cytochrome P450 activation to 4-hydroxycyclophosphamide. It's half-life is about 7 hours and its crosslinking effect may peak 6-12 hours after exposure. Cyclophosphamide can be metabolized to acrolein, which is toxic to the bladder.

Melphalan's structure is composed of nitrogen mustard linked to the amino acid phenylalanine. It was designed to be actively transported into th cell via the phenylalanine transporter, but it is taken up by the leucine transporter instead. Plasma half-life after IV administration is 90 minutes. Surprisingly, nausea and vomiting are infrequent with melphalan. It is very active against breast and ovarian cancers as well as myeloma.

busulfanOther Alkylating Agents

Other alkylating agents include busulfan, the chlororethylnitrosoureas and AZQ.

Busulfan is one of a series of alkyl sulfonates where the internal alkyl chain is 2-9 carbons long. It forms DNA crosslinks and is used to treat chronic granulocytic leukemia.

The chloroethylnitrosoureas include BCNU, CCNU, MeCCNU and the experimental agent chlorozotocin. They decompose under physiological conditions to produce alkylating moieties, which can further decompose to chloroethylcarbonium ions that produce DNA inter and intrastrand crosslinks and DNA-protein crosslinks.

BCNU structureThe chloroethylnitrosoureas are highly lipophylic and readily cross the blood-brain barrier, thus are the most widely used agents to treat brain tumors and leukemia, especially BCNU. A breakdown product, isocyanate, can inactivate some enzymes and is the major source of toxicity, especially renal in children.

AZQ strructureAziridylbenzoquinone, AZQ, was designed to be highly lipophilic in order to treat primary brain tumors. It is also reduces the number of blast cells in the cerebrospinal fluid of childhood leukemia patients. AZQ is though to be more active in hypoxic tumors because it is reduced under hypoxic conditions. The reduced AZQ produces strand breaks and DNA crosslinks.

Platinum Compounds

Cisplatin and carboplatin bind to DNA with high G-C content, and are thought to affect its template function. They act by a mechanism similar to alkylating agents, except they form platinum adducts instead of alkyl adducts.

cisplatin structureCisplating and carboplatin need to be hydroxylated by reacting with water before they can form adducts. Carboplatin reacts with water much slower than cisplating, thus its peak action is delayed about 12 hours compared with cisplatin. Both compounds can cur testicular cancer, and are also effective against cancer of the ovary, head and neck, and small cell lung cancer.

Binding to sulfur-containing molecules can prevent the reaction of platinum compounds with DNA. High intracellular concentrations of glutathione may confer resistance.

Both cisplatin and carboplatin are excreted via the kidneys, and are nephrotoxic. Hypertonic saline (NaCl is administered to pretect the kidneys. Cisplatin is not myelosuppresive, but may produce hearing problems or peripheral neuropathy.


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