Alkylating Agents

Alkylating agents were one of the earliest classes of drugs used to treat cancer, beginning in the 1940’s. The biggest weakness of most cancer cells is that they are very sensitive to DNA damage. Alkylating agents work by reacting with the proteins that bond together to form the very delicate double helix structure of a DNA molecule, adding an alkyl group to some or all of them. This prevents the proteins from linking up as they should, causing breakage of the DNA strands and, eventually, the death of the cancer cell. This phenomenon is essentially a mutation that takes away the cancer cell’s ability to multiply. While there are many different classes of alkylating agents, they all work by this same chemical mechanism. Alkylating chemotherapy drugs have this effect on a cancer cell during every phase of its life cycle, making them desirable for use on a wide range of cancers. The most benefit is seen in their use to treat cancers that grow slowly, like solid tumors and leukemia, but they are also used to treat lung cancer, ovarian cancer, breast cancer, lymphomas, sarcomas, myelomas, and Hodgkin’s disease. The five major categories of alkylating agents are nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines, and ethylenimines. In all cases, dosage and schedule are determined on an individual basis, considering the patient’s size, overall health, and the type of cancer being treated.

Nitrogen Mustards

Mechlorethamine, marketed under the trade name Mustargen®, is given by injection to treat Hodgkin’s disease and non-Hodgkin’s lymphoma, and as a palliative therapy for breast and lung cancers, and given as a topical treatment for skin lesions of mycosis fungoides (cutaneous T-cell lymphoma).

Ifosfamide, sold under the trade name Ifex®, is used to treat both Hodgkin’s and non-Hodgkin’s lymphoma, as well as recurrent testicular cancer and germ cell tumors, sarcomas, lung cancer, bladder cancer, head and neck cancer, and cervical cancer. It is administered intravenously.

Melphalan is a chemotherapy drug sold under the brand name Alkeran®, and is also referred to as L-PAM or phenylalanine mustard. It is used to treat multiple myeloma, ovarian cancer, neuroblastoma, rhabdomyosarcoma, and breast cancer. It comes as a 2 milligram pill to be taken daily on an empty stomach. More rarely, it can be administered by injection.

Chlorambucil is sold by the trade name Leukeran®, and is most widely used to treat chronic lymphocytic leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease. It has also been successfully used to treat non-Hodgkin’s lymphoma, breast, ovarian and testicular cancer, Waldenstrom’s macroglobulinemia, thrombocythemia, and choriocarcinoma. It comes in coated tablet form.

Cyclophosphamide is marketed as Cytoxan® or Neosar®, and is used to treat Hodgkin’s and non-Hodgkin’s lymphoma, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, t-cell lymphoma, multiple myeloma, neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing’s sarcoma; breast, testicular, endometrial, ovarian, and lung cancers. Because of the wide variety of cancers it treats, there is also a wide range of administering options. The most common methods are by intravenous injection or mouth in the form of tablets. Tablets should be taken with food and not tampered with. Less commonly, this drug is also approved to be injected directly into muscle, abdominal lining, or lung lining.

Nitrosoureas

Streptozocin is sold under the trade name Zanosar®, and is used to treat islet cell pancreatic cancer. It is given intravenously and can cause tissue damage if allowed to escape from the vein. Therefore, it is important for the person giving the treatment to have specialized training.

Carmustine is also known as BiCNU® or BCNU, and is used for some kinds of brain tumors, glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. It is also used in treatment for multiple myeloma, Hodgkin’s disease, non-Hodgkin’s lymphoma, melanoma, lung cancer, and colon cancer. Usually, this drug is given intravenously, but there is a solid form that can be placed inside the empty space left from the removal of certain brain tumors.

Lomustine, also known as CCNU or CeeNU®, is used to treat primary and metastatic brain tumors, Hodgkin’s disease and non-Hodgkin’s lymphoma, and has also been used for melanoma, lung, and colon cancer. It is made in 10 mg, 40 mg, and 100 mg capsules. It is typically taken once every 6 weeks, and it is important to take this drug with plenty of liquid and an empty stomach.

Alkyl Sulfonates

Busulfan, sold under trade names Busulfex® and Myleran®, is used to treat chronic myelogenous leukemia. It can be given in pill form or intravenously.

Triazines

Dacarbazine is sold under the trade name DTIC-Dome® and is used to treat metastatic malignant melanoma, Hodgkin’s disease, soft tissue sarcomas, neuroblastoma, fibrosarcomas, rhabdomyosarcoma, islet cell carcinoma, and medullary thyroid carcinoma. It is given intravenously, but can be irritating to the vein as well as any surrounding tissue it contacts. Therefore, it is important for the person giving the treatment to have specialized training.

Temozolomide is sold under the trade name Temodar®, and is used to treat the specific types of brain tumors anaplastic astrocytoma and glioblastoma multiforme. This medication comes in 5 mg, 20 mg, 100 mg, and 250 mg pills. It should be taken on an empty stomach with plenty of liquids, and not tampered with.

Ethylenimines

Thiotepa, known under the trade name Thioplex®, is an alkylating agent used to treat breast cancer, ovarian cancer, Hodgkin’s disease, and non-Hodgkin’s lymphoma. It is given by intravenous infusion

Altretamine is sold under the trade name Hexalen®, and is also called hexamethylmelamine or HMM. It is used to treat ovarian cancer. It is given in pill form and should be taken after meals.

Mechanism

These are cell-cycle nonspecific agents.  They attack the DNA at any point in the cell cycle.  They should never be used on pregnant women because they elevate the risk of birth defects.  These drugs work at the molecular level by binding to negatively charged sites on the DNA (oxygen, nitrogen, phosphorous and sulfur atoms).  This is called alkylation because the result of the chemical reaction is a DNA molecule with an attached chain of carbon atoms.  This extra strand impairs replication and division of strands of genetic matter.  The long DNA strands can break and the cross-linking needed for DNA replication can be inhibited.

The action of alkylating agents as chemotherapeutic drugs comes from their ability irreversibly bind to DNA and, once bound, the altered molecule disrupts the normal action and replication of the DNA strand. When this alkylation takes place at several places along the DNA molecule, the normal processes of the cell are interrupted. This leads to either to programmed cell death (apoptosis) or at least an arrest in cellular replication. In either case, when applied to cancer cells, alkylating agents can limit tumor growth and lead to tumor destruction.

Neoplasms can develop resistance to alkylating agents. This resistance has been linked, at least in part, to the expression of an enzyme known as MGMT (O6-MethylguanineDNAmethyltransferase). MGMT is able to repair DNA errors caused by alkylating agents. For example, temozolomide causes a potentially cytotoxic lesion in oxygen 6 of guanine nucleotides in DNA. MGMT enzymatically removes this methyl group, repairs the DNA, and negates the effect of the chemotherapy. In normal cells this would be advantageous; a cellular mechanism to prevent DNA disruption in cells that are normal physiologically. However cancers are also able to express this protein (and perhaps even overexpress it) thus rendering certain alkylating agents ineffective. Drugs that inhibit MGMT activity may be used as an adjunct to alkylating agents in order to overcome this resistance and improve the tumor-killing effect.

Some drugs are included in the alkylating agent class even though they do not technically add an alkyl group to the DNA.  The so-called Platinum drugs act as catalysts to include DNA linking even though they may not contribute the alkyl group.

Alkylating agents can also cause secondary cancers.  The most common one being (AML, or Acute Myeloid Leukemia) that can show up years after therapy stops.

Classes of alkylating antineoplastic agents
Nitrogen mustard analogues
Alkyl sulfonates
Ethylene imines
Nitrosoureas
Triazenes (Nonclassical)

Occasionally severe organ damage can occur with the administration of alkylating agents. Pulmonary fibrosis and veno-occlusive disease of the liver has occurred across all types of drugs within the class. The use of nitrosureas has been associated with renal failure.

The central nervous system can be affected by alkylating agents as well. In addition to severe nausea and vomiting common to the class, certain agents (e.g. Ifosfamide) is quite neurotoxic, leading to acute confusion and delirium, seizures, paralysis, and coma.

Alopecia (hair loss) is known to occur with alkylating agents. Sex organs are not spared—women that are treated with alkylating agents may experience permanent amenorrhea (lack of menstruation) and in men, sperm production may cease.

Nitrogen mustard analogues
Generic name Brand name Use in cancer Route
Mechlorethamine Mustargen Hodgkin disease, lymphosarcoma, certain leukemias, mycosis fungoides, and other cancers IV
Cyclophosphamide Cytoxan, Neosar Lymphoma, leukemia, and many carcinomas Oral (tablet, liquid), IV
Chlorambucil Leukeran CLL, Hodgkin and non-Hodgkin lymphoma, others Oral
Melphalan Multiple myeloma, as well as ovarian, breast, and prostate cancer Oral, IV
Ifosfamide Ifex Lymphoma, leukemia, testicular, and bladder cancers. IV
Trofosfamide Ixoten Cyclophosphamide prodrug
Estramustine Emcyt Advanced prostate cancer, conjugated with estradiol Oral

 

Alkyl sulfonates
Generic name Brand name Use Route
Busulfan Myleran CML, other blood cancers Oral
Treosulfan Ovastat (foreign) Busulfan analogue
Mannosulfan Busulfan analogue

 

Ethylene imines
Generic name Brand name Use in cancer Route
Thiotepa Thioplex

Girostan

Thiofozil

Tifosyl

Lymphoma and cancers of the breast, ovary, and bladder IV, Intrabladder, Intraperitoneal
Altretamine Hexalen

hexamethylmelamine

Treatment-resistant ovarian cancer Oral
Triaziquone Not used clinically
Carboquone Not used clinically

 

Nitrosoureas
Generic name Brand name Use in cancer Route
Carmustine Becenum

BCNU

Carmubris

Gliadel

Lymphoma, multiple myeloma, gliomas, and other types of cancer. IV

Implantable wafer (glioma)

Lomustine CCNU Cancers of brain, Hodgkin lymphoma Oral
Semustine Methyl-CCNU Related to carmustine
Streptozocin Zanosar IV
Fotemustine Muphoran (foreign)
Nimustine ACNU

Nidran

Ranimustine Cymer (foreign)

Cymerin (foreign)

 

Triazenes (Nonclassical)
Generic name Brand name Use in cancer Route
Dacarbazine DTIC-Dome Hodgkin’s lymphoma, malignant melanoma IV
Temozolomide Temodar Cancers of brain including anaplastic astrocytoma, glioblastoma multiforme (GBM), and gliomas. Oral, IV