Download Alkylating agents

Drug
Class
MOA
Anti-cancer Agents
Toxicity/Side fx
Mechlorethamine
Alkylating agents
(Nitrogen mustard)
Alkylation of DNA, esp. at the N7
atom of guanine
Cyclophosphamide
Alkylating agents
(Nitrogen mustard)
Activated by liver P450 to acrolein
(toxic) and phosphoramide mustard
(therapeutic). Alkylates DNA.
Carmustine
(or BCNU)
Alkylating agents
(Nitrosureas)
Inhibits RNA, DNA and protein
synthesis via alkylation
Methotrexate
Antimetabolites
(Folic acid analog)
Mercaptopurine
and Thioguanine
Antimetabolites
(Purine analogs)
5-Fluorouracil
(5-FU)
Antimetabolites
Vincristine
(Oncovin)
Natural products
Vinca alkaloids
Taxol®
(= paclitaxel)
Natural products
Doxorubicin
(Adriamycin)
Antibiotics
Anthracyclines
Bleomycin
Antibiotics
Dactinomycin
Antibiotics
Complex with Fe/O2, binds to DNA,
induces strand breakage.
Intercalating agent: inhibits gene
transcription (RNA pol II).
Etoposide (VP-16)
Epipodophyllotoxins
Not sure.
L-Asparaginase
Enzyme
Deprives cells of exogenous
asparagine, inhibiting protein
synthesis.
(Pyrimidine analog)
Tetrahydrofolate analog, inhibits
dihydrofolate reductase and thus
prevents synthesis of thymidylate
and purines for DNA
Feedback inhibition of de novo purine
synthesis, interconversion enzymes: ↓
purine levels causes ↓ DNA, RNA
and glycoprotein synthesis
Activated by conversion to deoxy
form; Blocks thymidylate synthetase
and lowers cellular dTTP (↓DNA
synthesis) and is directly incorporated
into RNA, interfering with RNA
processing and translation.
Anti-mitotic agent with metaphase
arrest by binding to tubulin: prevents
assembly of microtubules.
Anti-mitotic agent that binds to
microtubule polymer and prevents
depolymerization.
(Proposed): Intercalates into DNA,
inhibits DNA topoisomerase II.
Also generates oxygen free radicals.
Special Considerations
Hematological &
immunosuppressive fx,
epithelial cell toxicity, N/V
Same as above, plus:
Hemorrhagic cystitis in 510%.
Profound, delayed
myelosuppressive fx. (Most
suppression ~ 6 wks after
treatment)
Leucovorin rescue: a
reduced folate can prevent
toxic effects to patient w/high
doses of MTX.
Part of MOPP regimen; Administered IV; most rapidlyacting N-mustard; Used to suppress malignant effusions,
ascites due to cancer.
Well-absorbed orally, so used more often than
mechlorethamine. FAC post-op adjuvant for breast cancer.
Co-administer mesna (reducing agent) to ↓ toxic effects!
Myelosuppression, mucositis,
diarrhea, nausea.
Neurologic toxicity.
Administered IV, rapidly inactivated in liver.
FAC post-op adjuvant for breast cancer.
Neurotoxicity (microtubule
formation needed for axonal
transport!)
Administered IV, metabolized by liver, excreted in bile.
Part of MOPP regimen.
ALL treatment
Promising results in treatment of ovarian and breast
cancer, malignant melanoma.
Note opposite mechanisms of Vincristine and Taxol!
Administered IV, rapidly taken up by all tissues except
brain. Used for leukemias, breast & ovarian cancer.
ABVD, FAC regimens.
Co-administer Dexraoxane: a cardioprotective agent,
counteracts ROS formation by chelating Fe.
ABVD regimen, also MOP-ABV. For lymphomas,
squamous cell carcinomas.
Valuable drug in cure of childhood cancers: Wilm’s
tumor, rhabdomyosarcoma, Ewing’s & Kaposi sarcomas.
Myelosuppression, alopecia.
Chronic cardiomyopathy:
CHF, unresponsive to
digitalis, may be irreversible
Pulmonary fibrosis (“Bleo
lung”); low myelosuppress.
Very myelosuppressive;
extreme care needed in setup
of IV: wound could be lethal.
Myelosuppression is dose
limiting.
High lipophilicity, so good for brain tumors, meningeal
leukemias.
Very polar: doesn’t cross BBB; Well-absorbed orally;
Polyglutamation occurs intracellularly and blocks efflux.
Curative for choriocarcinoma, backup regimen for breast
caner, also for ovary, bladder, ALL.
Testicular cancer, SCLC (small-cell lung carcinoma) and
Non-SCLC; Synergizes nicely with platins (no
overlapping toxicity.
Only enzyme used in cancer treatment.
Certain neoplastic cells (such as in ALL) require an
exogenous supply of asparagine, unlike most normal
tissue.
Drug
Class
Cisplatin
Platinum
coordination
complexes (platins)
Hydroxyurea
(Misc.)
Procarbazine
(Misc.)
Tamoxifen
Anti-hormones
(Anti-estrogen)
Prednisone
Hormones
Adrenocorticosteroids
MOA
Toxicity/Side fx
Pt complex with DNA (N7 of guanine
again), causes inter- and intrastrand
crosslinks
Extremely emetic!
Renal dysfunction: extensive
hydration required; occasional
ototoxicity; Unique feature:
little myelosuppression.
Inhibits ribonucleotide reductase
(rNTP→ dNTP), and thus DNA
synthesis
Alkylating activity and free radical
generation.
Competitive inhibitor for estrogen
receptors in breast (partial agonist in
cervical tissues). ↓ estrogen
stimulation of cell proliferation.
Potent lympholytic activity: induces
apoptosis
Special Considerations
Synergy with etoposide.
Administered IV; Pt persists in tissues for months
Myelosuppression
Highly lipophilic: crosses BBB
MOPP regimen for Hodgkin’s disease.
Minimal
Extremely useful in tx of breast cancer (50% response);
clinical trials for chemoprevention in high-risk women.
Treatment of ALL (w/vincristine), malignant lymphoma
(MOPP regimen) in children.
Beneficial in advanced breast cancer, manangement of
paraneoplastic hypercalcemia.
ALL =
Acute lymphoblastic leukemia
MOPP =
Mechlorethamine, Oncovin (vincristine), Procarbazine, Prednisone. For Hodgkin’s disease stage III or IV.
ABVD =
Adriamycin (doxorubicin), Bleomycin, Vinblastine (the “other” vinca alkaloid), Dacarbazine.
This is regimen of choice for Hodgkin’s disease stage III or IV.
FAC =
5-FU, Adriamycin (doxorubicin), Cyclophosphamide. Reduces relapse rate after breast cancer surgery (w/nodal involvement)
Administration of hematopoeitic growth factors like G-CSF can counter chemo-induced myelosuppression and allow dose intensification.