Antineoplastic Agents

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MECHLORETHAMINE

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Alkylating Agent

MOA: Ring opening, depurinization, miscoding, cross-linking

Powerful vesicant

Tx: Na+ thiosulfate (donates e-)

USES: MOPP:
M = mechlorethamine
O = vincristine (Oncovin)
P = procarbazine
P = prednisone

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CYCLOPHOSPHAMIDE

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Alkylating Agent

MOA: MOA: Ring opening, depurinization, miscoding, cross-linking

Leukopenia- increases risk of infection. thus use:

Filgrastim- G-CSF
Sargramostim- GM-CSF

Avoid Hemorrhagic Cystitis with hydration and MESNA (reacts with acrolein)

SIADH- tx- furosemide

Front 3

Nitrosoureas

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Alkylating agents

MOA: alkylate DNA and Carbamoylate proteins. Not vesicants. Lipophillic (BBB). Attack oxygen. Not phase specific but effects in S phase.

Hint 3

carmustine

lomustine

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METHOTREXATE

Back 4

Antimetabolite (folic acid analog)

MOA: inhibits DHFR and,
in doing so, causes depletion of FH4 and,therefore, of 1-carbons groups to donate to dUMP. As a result, synthesis of TMP grinds
to a halt.

Polyglutamated in cell (trapped)

High dose with Leucovorin (rescues healthy cells)

Effects seen in S phase

Front 5

Cytarabine

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Pyrimadine Analog

MOA: It incorporates into DNA in place of dCTP causing:

a) steric hindrance to rotation of the pyrimidine base around its nucleoside bond causing improper stacking of base pairs. In turn, this causes fragmentation of the double helix.

b) inhibition of elongation when it incorporates at the terminal position.It is also an potent inhibitor of DNA polymerase.

SIDE EFFECT: Myelosuppression is dose-limiting.

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6-MP

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Purine Analog

MOA: 6-T-IMP:
a) incorporates into DNA & RNA
b) inhibits conversion of IMP -> AMP
c) forms 6-THIO-GMP that incorporates into DNA
NET EFFECT: inhibits transcription & replication

Hint 6

Use with allopurinol

Inhibits 6-MP to 6-T-uric acid which increases efficacy and toxicity.

Also prevents high uric acid from purines following cell death

Prevents:
Hyperuricemia- gout
hyperuricosuria- renal calculi

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VINCRISTINE

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Vinca Alkyloid

MOA: bind tublulin and dissolve. disrupts mitotic spindle (metaphase arrest) and axon transport and phagocytosis (neurotox)

MOPP

SIDE EFFECTS: - Neurotoxicity -> paresthesias (numbness & tingling) in extremities
- Autonomic neuropathy can occur early in treatment -> abdominal pain,

Loss of Achilles tendon reflex can be permanent.

OTHER SIDE EFFECTS: Alopecia (20% of patients)
-
Rarely, SIADH causing dilutional hyponatremia.

Hint 7

CAUTION: SEVERE PAIN ON EXTRAVASATION from PHLEBITIS

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DOXORUBICIN

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Antibiotic

MOA: The anthracycline ring intercalates between any 2 base pairs in opposite strands of DNA causing local uncoiling of the double helix which interferes with the ability of topoisomerase II to re-anneal the strands. This causes STRAND BREAKS.

Broad spectrum against cancers

AVOID EXTRAVASATION - Severe local vesicant action causes erythematous streaking near the infusion site referred to as the ADRIAMYCIN FLARE.

SIDE EFFECTS: -
It turns urine red.
leukopenia

Hint 8

Cardiotoxicity:

Quinones attached to the anthracycline ring form semiquinones that chelate iron forming an Rx-Fe-DNA complex that reacts with O2 -> superoxide (O2-) & hydroxyl (OH) radicals that cause strand breaks and membrane peroxidation. The heart is prone to toxicity b/c it has low levels of the detoxifying enzymes superoxide dismutase & catalase. The risk of cardiotoxicity is greater in patients who have undergone radiation therapy or other chemotherapy.

** DEXRAZOXANE (Zinecard) is an iron chelator used to ↓ the cardiotoxicity w/o blocking the antitumor effect. This works b/c doxorubicin-induced lipid peroxidation is iron dependent.

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ALEMTUZUMAB

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Biological Response Modifiers

is a chimeric rat-human IgG variant used for B-cell CLL that targets the CD52 antigen on the surface of B & T lymphocytes and other cells. Lysis of leukemic cells is achieved through antibody- & complement-dependent cytotoxicity.

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Y- IBRITUMOMAB TIUXETAN

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Biological Response Modifiers

MOA: Binds CD-20 antigen on most B cell neoplasms

Tiuxetan is a chelator covalently linked to the antibody ibritumomab that tightly binds the radioisotope that emits high energy β particles that destroy the cell from inside. The ibritumomab induces apoptosis.

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THALIDOMIDE

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MISC

MOA: is used to treat multiple myeloma. It inhibits angiogenesis and has antiinflammatory and immunomodulatory activity. It decreases TNF-α synthesis and inhibits leukocyte migration. Otherwise, its antineoplastic mechanisms are unclear. It is highly teratogenic (Pregnancy Category X).

Hint 11

LENALIDOMIDE-is a less teratogenic

POMALIDOMIDE -Pregnancy category X. Available only through a special manufacturer’s program.

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DENILEUKIN DIFTITOX

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MISC

MOA: immunotoxin formed by recombination of IL-2 with diphtheria toxin that binds to high-affinity IL-2 receptors. Cells that express lower affinity receptor are less sensitive to this drug.

Fragment A inhibits peptide chain elongation during protein synthesis whereas Fragment B binds to specific host cell receptors & facilitates entry of Fragment A. The net effect of denileukin is cell death.

SIDE EFFECTS include hypersensitivity and vascular leak syndrome.