1. Nitrogen mustards
2. Ethyleneimines
3. Alkyl sulfonates
4. Nitrosoureas
5. Triazenes

• Binds two DNA strands -- crosslinks DNA
• Alkylation can open the imidazole ring in guanine
• Alkylation can cause stabilization of the enol tautomer of thymine, resulting in three hydrogen bonding sites with guanine --> results in base pair mismatch
• The cell may respond to alkylation by excising the alkylated guanine in an attempt to repair the DNA strand

• Caspases breakdown nucleus membrane and cytoskeleton proteins and activate other factors in apoptosis pathway
• DNA is fragmented by endonucleases
• Cells that have undergone apoptosis are removed by phagocytes

Bone Marrow Suppression

• Often dose limiting
• Immune (humoral and cellular) suppression is a consequence dramatically increasing the probability of infection

Mucosal

• Increases risk of bacterial sepsis

CNS

• Emesis through activation of CTZ in CNS
• The cytotoxic effect on GI epithelial cells can also cause emesis days after administration

Carcinogenic

• Some alkylating agents can increase risk of developing leukemia and other types of cancer
• This effect is observed years after therapy

Other

• Less predictable are pulmonary fibrosis, hepatic veno-occlusion, and renal toxicity

• Mechlorethamine
• Cyclophosphamide
• Ifosfamide
• Melphalan
• Chlorambucil

Uses

• Leukemia
• Lymphomas

ADR

• More gradual myelosuppressive onset
• May cause Acute Myelogenous Leukemia

• Multiple Myeloma
• Epithelial ovarian cancer

• Increased number of plasma cells (mature B-cells) in the bone marrow
• Bone lesions (caused by inflammation response in bone)
• High serum levels of antibody (usually IgG)

• Bone lesions are believed to be caused by interaction of plasma cells with bone stromal cells, which results in activation of stromal cells
• The stromal cells in turn activate the osteoclasts which destroy bone

Uses

• Leukemia
• Lymphoma
• Multiple Myeloma
• Ovarian cancer
• Breast cancer
• Neuroblastoma

ADRs

• Accumulation of metabolite, Acrolein, in the bladder causes hemorrhagic cystitis --> hydration and adminstration of Mesna reduces hemorrhagic cystitis
• Bladder fibrosis with or without cystitis
• SIADH rare

• Adminstration of Mesna
• Hydration

Uses

• Testicular cancer
• Sarcomas

ADRs

• Accumulation of metabolite, Acrolein, in the bladder causes hemorrhagic cystitis --> hydration and adminstration of Mesna reduces hemorrhagic cystitis

Uses

• Leukemia
• Lymphomas

ADRs

• Very reactive, vesicant
• Extravasation concern (treat with thiosulfate)

MOA

• Inhibits microtubule polymerization
• Binds to microtubule-binding protein

ADRs

• Has an estrogen moiety, thus has estrogenic activity
• Impotence, gynecomastia, fluid retention

• Effective against resistant cells due to p53 inactivation --> tumor cells use base excision repair as resistance mechanism
• Chronic Lymphocytic Leukemia
• Indolent B-cell Non-Hodgkins Lymphoma

MOA

• Potentially tri-functional alkylating agent
• Thought to react with guanine N7 and release free radicals which break the glycosidic bond between base and deoxyribose --> alkylated guanine is release

Uses

• Parent drug directly infused into bladder for bladder cancer treatment
• Ablation of bone marrow before stem cell transplantation

ADRs

• Cross BBB --> neurotoxic side effects

MOA

• Uncertain --> thought that metabolites (formyl group) may have alkylating activity

Uses

• Ovarian cancer

ADRs

• Cytotoxicity attributed to metabolites
• Ataxia
• Mood change
• Confusion
• Dizziness
• Neurotoxic effects are reversible (pyridoxine, a vit B6 derivative may decrease neurotoxic effects, but not thoroughly investigated and it may decrease anti-tumor response)

MOA

• Selective for killing myeloid lineage cells
• Intra-strand (not inter) DNA crosslinking observed using virus DNA
• High reactivity with thiols (sulfur stripping) may have therapeutic effect

Uses

• Chronic Myelogenous Leukemia
• Bone Marrow Suppression

ADRs

• Pulmonary fibrosis and liver veno-occlusion at high doses

MOA

• A triazene
• Adds methyl group to O-6 of guanine which can result in mispairing (G-T)
• Cell cycle non-specific

Uses

• Metastatic Melanoma
• Hodgkin's Disease

ADRs

• Onset of emesis can occur within hours or be delayed by days due to GI epithelial damage
• Myelosuppression common

• Transversion --> a permanent mutation results (A-T instead of G-C)
• Strand break (the nucleotide on the opposite strand of the methylated G is removed)

MOA

• Lipophilic enters CNS
• O-6 methylation on guanine
• Parent drug has ability to crosslink DNA
• Carbamoylation of proteins can occur as well

Uses

• Gliadel wafers (carmustine) are effective for brain tumors (gliomas)

Mechanism of Resistance

• Tumor cell produces AGT which removes methyl group on O-6 of guanine

MOA

• Glucose moiety enhances uptake of drug into islet cells of the pancreas by GLUT transporter
• The methylnitrosourea moiety alkylates DNA

Uses

• Metastatic islet cell carcinoma

ADRs

• Bone marrow suppression
• Diabetes mellitus (animal models)

• Increased intracellular concentration of nucleophiles
• Increased production of DNA repair mechanisms (base excision, AGT expression, nucleotide excision less likely)
• Enzymatic drug inactivation (ie, cyclophosphamide by aldehyde dehydrogenase)