Chemotherapeutic agents

This is a brief overview of chemotherapeutic agents, their mechanism of action, and some related side effects.

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ADDITIONAL TAGS:
Chemotherapeutic agents
Classes of chemical agents used in the treatment of cancer
Alkylating agents
Antimetabolites
Microtubule targeting agents
Topoisomerase inhibitors
Anthracyclines
Monoclonal antibodies
Other agents

Alkylating agents
Attach alkyl groups to DNA, allows cross linking of base pairs, damaging DNA; cell cycle nonspecific
Typical alkylating agents: cyclophosphamide, ifosfamide, melphalan, busulfan, mechlorethamine, chlorambucil, thiotepa
Side effects: myelosuppression drop in WBC, Hb, crit, nausea/vomiting, secondary malignancies, infertility/impaired fertility, hemorrhagic cystitis hematuria, dysuria from direct irritation of bladder by acrolein metabolite
Atypical alkylating agents
Platinum compounds covalently bind purine DNA bases. Drugs and side effects:
cisplatin causes nephrotoxicity and n/v
carboplatin causes thrombocytopenia
oxaliplatin causes cold sensitivity
all cause peripheral neuropathies, paresthesia
Nitrosoureas: BCNu, CCNu both cause pulmonary toxicity, phlebitis. CNS
Alkylating agents
Antimetabolites
Microtubule targeting agents
Topoisomerase inhibitors
Anthracyclines
Monoclonal antibodies
Other agents

Antimetabolites
Inhibit DNA replication or repair by mimicking normal cell compounds; S phase specific
Folate inhibitor: Methotrexate inhibits DHFR, prevents regeneration of THF
Adjuvant leucovorin to protect healthy cells adjuvant
Side effect is mucositis, myelosuppression
Pyrimidine inhibitors
5-fluorouracil inhibits thymidylate synthetase
Bolus dose causes myelosuppression
Continuous dose causes GI problems mucositis, diarrhea
Synergistic leucovorin potentate mechanism of action synergistic
Capecitabine is essentially an oral prodrug for 5-FU
Side effect: hand-foot syndrome - palms and hands and feet become red, can start blistering
Cytarabine AraC is a DNA chain terminator
Side effects: conjunctivitis and cerebellar neural defects
The 7 in 7+3 chemotherapy
Purine analog is 6-mercaptopurine
Alkylating agents
Antimetabolites
Microtubule targeting agents
Topoisomerase inhibitors
Anthracyclines
Monoclonal antibodies
Other agents

Microtubule targeting agents
These drugs inhibit mitosis, specifically M phase
Vinca alkaloids destroy microtubules, obviously preventing their function
Vincristine, vinblastine, and vinorelbine
Side effects: peripheral neuropathy, myelosuppressive blast others
Fatal if given intrathecally
Taxanes stabilize microtubules, preventing their function
Paclitaxol, docetaxol
Side effects: myelosuppression, peripheral neuropathies
Hypersensitivity
from diluent: Cremophor diluent in paclitaxel Tween80 in docetaxel
Avoid hypersenitivity with abraxane, protein-bound paclitaxol particles
less sensitivity but more neuropathy

Topoisomerase inhibitors
Topoisomerase I inhibitors prevent relaxation of supercoiled DNA
Topotecan, irinotecan
Both have side effect of myelosuppression
Irinotecan causes diarrhea: “I ran to the canâ€
Topoisomerase II inhibitors prevent recoiling of DNA after transcription
Etoposide, teniposide
Both have side effects of myelosuppression, mucositis, secondary malignancies AML
Etoposide also causes hypotension

Anthracyclines
Various mechanisms of action: intercalate DNA, inhibit topo II, generate ROS, perhaps alkylation
-rubicins: doxorubicin, daunorubicin, idarubicin, epirubicin
Side effects: biventricular heart failure, necrotic with extravasation
The 3 in 7+3 chemotherapy


Monoclonal antibodies
Origin determined from suffixes: -omab from mouse; -ximab is chimeric cross between human/mouse; -umab is humanized; -mumab is fully human
mAb
Target
Treats:
Toxicity
Rituximab
CD20
lymphoma
-
Trastuzumab
Her-2
breast cancer
-
Cetuximab
EGFR
solid tumors initially for colorectal cancer
Acneiform rash
Bevacizumab
VEGF
solid tumors initially for colorectal/lung cancers
GI perforation,

Other chemotherapeutic agents
Bleomycin causes lung toxicity
Side effects: pulmonary fibrosis, interstitial pneumonitis, hypersensitivity pneumonitis cough, infiltrates
Hormonal therapies
Antiestrogens block estrogen stimulation of breast cancer
Tamoxifen, fulvestrant, megestrol acetate
Aromatase inhibitors block synthesis of estrogen
Anastrozole, letrozole
Antiandrogens block androgen stimulation of prostate cancer
Other targets for prostate cancer are LHRH agonists prevent testosterone production, GnRH antagonist, CYP17 inhibitor