Anti-Cancer Drugs Flashcards
Active Cell Phases
M Phase - Mitosis and Cell Division
S Phase - DNA snythesis
Antimetabolites
Inhibit nucleic acid synthesis
Inhibit DNA replication
Mercaptopurine Basics
Analog of purine bases hypoxanthine or adnine; thiopurine
6-MP is converted to T-IMP, which is a poor substrate for guanylyl kinase.
T-IMP accumulates in cells and inhibits purine synthesis
Mercaptopurine Details
Extensive first-pass metabolism by xanthine oxidase in liver limits to <20% of administered dose
Allopurinol (XO inhibitor) increases absorption by five-fold
Folic Acid Analog
Methotrexate
Irreversibly binds and inhibits dihydrofolate reductase (DHFR).
Prevents FH2 from converting to FH4 during DNA synthesis.
Synthesis of thymidine and purines inhibited.
Methotrexate Details
Used in cancers and autoimmune diseases.
Toxicities are frequent: including myelosuppression, GI
Photosensitivity. Long term use cause hepatic and renal toxicity.
Leucovorin
Folinic acid, a derivative of FH4
Usually administered 12-20h following the end of MTX infusion to mitigate toxicities.
Pyrimidine analog
5-fluorouracil (5-FU)
Metabolized to ribosyl (F-UTP) and deoxyribosyl-(F-dUMP)
F-UTP is incorporated into RNA and interferes with RNA function
F-dUMP inhibits thymidylate synthase, inhibiting synthesis of thymidine (DNA synthesis inhibited)
5-Fluorouracil Details
Used for solid tumors; topical use for noninvasive skin cancer
Side effects include: myelosuppression, GI mucosal damage leading to ulcerations in mouth and diarrhea. Photosensitivity
Pyrimidine Analog: Cytarabine
Analog of cytosine with modified sugar moeity. Converted to triphosphate form and incorporated into DNA in place of cytosine
Uses: Leukemia
Toxicity: Myelosuppression, GI toxicity.
Hydroxyurea
Inhibits ribonucleotide reductase, which is needed for production of deoxyribonucleotides
Prevents sickle-shaped cells from forming by increasing HbF synthesis
Use: Sickle-cell anemia, myeloproliferative disorders
GI toxicities, myelosuppression, anemia, bleeding, secondary leukemias.
Summary of Antimetabolites
Inhibit DNA synthesis by various mechanisms
Mercaptopurine is a purine analog that is converted into T-IMP, which accumulates, is not recognized by guanylyl kinase, and blocks synthesis of puranes
Methotrexate is an example of a folic acid analog; inhibits DHFR
5-FU is a pyrimidine analog that is converted into F-dUMP and F-UTP, inhibiting DNA synthesis and RNA function respectively.
Hydroxyurea inhibits ribonucleotide reductase
Anti-microtubules
Either inhibit tubulin polymerization or stabilze microtubules to block mitosis. M phase-specific agents
Vinca Alkaloids
Vincrisine, vinblastine, vinorelbine
Specifically bind to tubulin and inhibit tubulin polymerization into microtubules, blocking spindle formation.
Toxicities: Myelosuppression, GI toxicity, peripheral neuropathy.
Taxanes
Paclitaxel, docetaxel
Bind beta-tubulin subunit, promoting assembly of microtubules and preventing depolymerization.
Uses: Solid tumors
Toxicities: Severe alopecia, myelosuppression, peripheral neuropathy, neutropenia, anemia
Cytotoxic Antibiotics
Derived from streptomyces bacteria
Act directly on DNA
Block Mammalian cell division
Anthracyclines
Doxorubicin, Daunorubicin
Contains an anthracene ring complex
Intercalate into DNA, deforming the structure and interfering with DNA and RNA synthesis
Inhibit topoisomerase II activity, blocking repair of DNA breaks
Contain quinone moieties, which induce the production of free radicals.
Anthracycline Details
Use: Primary chemotherapy for breast cancer. Also Hodgkins disease, bladder, overian, and gastric carcinoma
Daunorubicin is primarily for acute myeloid leukemia
Toxicities: Cumulative, dose-related cardiac damage, severe or total hair loss, GI mucosal damage
Bleomycin
Blenoxane, Cipla, Bleocip
Family of structurally metal-chelating glycopeptides Requires metal and oxygen for activity Chelates metals (usually iron) and reacts with O2 to produce free radicals that cause DNA damage
Bleomycin Details
Uses: Testicular, ovarian, Hodgkin’s lymphoma, head and neck cancer.
Unique mechanism of action
Toxicity does not overlap with other dugs
Almost no myelosuppression
Causes pulmonary fibrosis
Inactivated by bleomycin hydrolase (found everywhere but skin and lung)
Alkylating Agents
Agents that covalently attach alkyl groups to DNA, causing cross-linking.
Include: Nitrogen mustards, nitrosoureas, busulfan, cisplatin
Nitrogen Mustards; Cyclophosphamide
Low doses are immunostimulatory and antiangiogenic
High doses are cytotoxic and immunosuppressive
Cyclophosphamide metabolized to produce 4-hydroxycyclophasphamide and aldophasphamide
Aldophosphamide is metabolized to phosphoramide mustard, which crosslinks nucleic acid molecules
Platinum Agents: Cisplatin
Platinum binds DNA to form intra- and inter-strand cross-links/adducts with purine bases, disrupting DNA synthesis and inducing cell death.
Uses: 1st line for testicular, ovarian, bladder, also used for melanoma
Toxicities: Nephrotoxicity due to reactive oxxygen species
One of strongest emetogenic
Ototoxicity
SERMS (selective estrogen receptor modulator)
Tamoxifen
Used to treat ER+ (estrogen receptor) breast cancer
Binds to ER and blocks estrogen binding
Side effects: Blood clots and stroke, endometrial and uterine cancers
SSRI antidepressants interfere with metabolism
Aromatase Inhibitors
Anastrozole
Nonsteroidal competitive inhibitors of the enzyme aromatase
Aromatase converts androgens to estrogens.
Targeted Therapies Imatinib
Small molecule tyrosine kinase inhibitor
Toxicities: nausea, vomiting, cramps, rash and diarrhea
Targeted Therapies Trastuzumab
Blcoks mitogenic, proliferative, and anti-apoptotic effectrs of HER2 signaling
1st line therapy for HER2-overexpressing metastatic breast cancer.
Cardiotoxicity
Targeted Therapies: Bevacizumab
Vascular endothelial growth factor stimulates angiogenesis. Bevacizumab is monoclonal antibodies against VEGF
Inhibits new vessel development
First line therapy in combination with chemotherapy for metastatic colorectal, breast, and NSCLC
Toxicities: HTN, increased risk of bleeding, bowel perforation.
