06 Anticancer drugs Flashcards
Therapeutic modalities
Surgery and radiation therapy: localized, solid tumor
Drug therapy: systemic
Cell cycle drugs
CELL CYCLE-SPECIFIC DRUGS
kills cells within cell cycle
toxicity is proportional to the length of exposure, schedule specific
Methotrexate (s phase specific)
High growth fraction (ex. leukemia and lymphoma)
CELL CYCLE NON-SPECIFIC kills cells in and out of cell cycle toxicity is dose-dependent high and low growth fraction tumors alkylating agents and antitumor antibiotics except bleomycin
Gompertzian growth
Growth is fast but it slows down as time passes
cells compete for common/limited blood supply
advanced cancers are less responsive to chemo
Debulking procedure: surgery lessens tumor, remaining cells are stimulated to proliferate again = more sensitive to drugs
Gompertzian growth graph: diagnosis at 10^9-10^10 (too late), early diagnosis,
Cardinal rule of chemo: curability is inversely proportional to cell number
Cell kill
Log-kill or log cell-kill: A constant fraction of cells is given drug dose, not by a constant number
drugs used in chemo cannot be given continuously
Log cell-kill graph: surgery + adjuvant chemotherapy vs chemo vs late diagnosis with chemo
Factors affecting cell kill
Dose intensity and schedule: cannot tolerate -> reduce/delay dose
Drug resistance
Tumor site
Performance status
Drug selection
Single drug: choriocarcinoma, burkitt’s lymphoma
Combination: circumvents drug resistance, maximizes tumor cell kill
Guidelines: each drug should have some effectivity, different MOAs to prevent resistance, minimal overlapping toxicities
Lung = ECV
Breast = CMF
Acute lymphoblastic leukemia = COAP
General toxicity
Myelosuppression
dose-limiting toxicity
leukopenia > thrombo > anemia
exception: vincristine, bleomycin, streptozocin, hormones, asparaginase, cisplatin
Nausea and vomiting: CNS in origin, serotonin antagonists
Cytotoxicity to other cells: stomatitis, diarrhea, alopecia, infertility
Mechanism of acquired resistance
Improved DNA repair Dec in drug activation inc in drug inactivation dec in cellular uptake inc in p-glycoprotein -> inc in efflux
Antimetabolites: folic acid analogs
MOA: Activated intracellularly by FPGS -> polyglutamate metabolites
inhibit thymidylate synthesis
inhibit de novo purine synthesis
inhibit AA synthesis (serine and methionine)
PemeTREXed, pralaTREXate
MethoTREXate:
MOA: competes for folic acid in DHFR -> inhibit thymidylate and purine synthesis -> inhibition of DNA, RNA, protein synthesis
parenteral form, but not cross BBB (administer in subarachnoid space)
Toxicity: leucovorin
Antimetabolites: purine and pyrimidine analogs
1 Mercaptopurine (purine):
MOA: needs HGPRT -> monophosphate (inhibits de novo synthesis) + triphosphate (replaces guanine)
oxidized in liver by xanthine oxidase
allopurinol: xanthine oxidase inhibitor (= lessen dose of 6MP)
2 Thioguanine (purine)
3 Fluorouracil (pyrimidine): MOA: FdUMP = binds to an inhibits thymidylate synthase -> death FUTP = in RNA FdUTP = in DNA
4 Cytarabine (pyrimidine): MOA: block DNA synthesis and incorporate into DNA and RNA for hematologic malignancies
5 Gemcitabine:
MOA: block DNA synthesis, for solid and hematologic malignancies
Alkylating agents
MOA: form covalent bond with electron rich site -> DNA fragmentation (N7 site of guanine -> depurination and excision of guanine residues), cross-linking (no uncoiling prevents replication), mispairing
ANTman N Phoebe
Alkyl sulfonate, Nitrosoureas Triazine, Nitrogen mustards, Platinum coordination complexes
Nitrogen mustards
Cyclophosphamide
broadest spectrum
inactive -> liver -> cells -> cytotoxic phosphoramide and acrolein
oral, IV, IM
adverse: alopecia, sterile hematuria (accumulation of acrolein)
antidote: MSNa
Melphalan
Chlorambucil
Ifosphamide
Mechlorethamine
Adverse effects of alkylating agents
Bone marrow suppressio Vesicant effects (blistering) gonadal damage, azoospermia hemorrhagic cystitis nuerotoxicity pulmonary toxicity (fibrosis and death) nephrotoxicity mutagenic, carcinogenic, teratogenic
Cytotoxic antibiotics
MOA:
1 bind to DNA via intercalation 2 blocking DNA/RNA synthesis
3 DNA strand scission (generate free radicals and complex with topoisomerase II)
Adverse effects: tissue irritation, local tissue necrosis, cardiotoxicity (superoxide dismutase for free radicals), blisters, erythema, pulmo toxicity, mucocutaneous reactions, radiation recall reaction
Anthracycline, bleomycin
Adriamycin flare (-rubicin drugs): erythematous leak oven skin
rubicin: red urine and sclera
mitoxantrone: blue urine and sclera
Natural products
Mitotic inhibitors: act on M-phase
vinca alkaloids: VINcristine, VINblastine
taxanes: pacliTAXel, doceTAXel
Topoisomerase inhibitor:
camptothecins: irinotecan, topotecan
podophyllotoxins: etoposide, teniposide
Natural products: mitotic inhibitors
VINCA ALKALOIDS
MOA: binds to tubulin -> inhibit microtubule assembly -> disruption of microtubule processes
CNS toxicity, bone marrow suppression
TAXANES
MOA: promote microtubule formation, inhibit depolymerization/assembly
Natural products: Topoisomerase inhibitors
CAMPTOTHECINS
MOA: binds to DNA Top I complex
PODOPHYLLOTOXINS
MOA: inhibits Top II
Hormones
Glucocorticoids (prednisone) Antiestrogens (tamoxifen) antiandrogens GnRH agonists estrogens progestins androgens
Cytokines uses in immunotherapy
Interferon-a: CML and Kaposi’s sarcoma
IL-2: renal cell carcinoma and melanoma
BDG vaccine:
Immune checkpoint inhibitors
MOA: blocks proteins made by immune system cells -> T cells can kill cancers better
Anti CTLA-4: binds to CTLA-4 so T cell can bind to C28 -> activation, Ipilimumab
Anti PD-1: if tumor cell binds to PD1, lysis is inhibited; Pem binds to PD1 to block the inhibitor, Pembrolizumab
Anti PDL1: Atezolizumab binds with PDL1 to kill tumor cell
Chimeric antigen receptor t-cell therapy
Change T cells to kill cancer cells
Tisagenlecleucel
MOA: expresses CAR that recognizes B cell antigen CD19 for B-cell NHL and ALL
Targeted therapies
TKIs: imatinib, nilotinib, dasatinib
inhibit multiple enzymatic sites
12-24h plasma half life
MAbs: rituximab
specific for single receptor
long plasma half life
TKIs (nibs)
Prevents phosphorylation of substrate kinase by ATP
Inhibits BCR-ABL (oncoprotein), c-kit (GI stromal tumor), PDGFR tyrosine kinases
Target of MABs and TKIs
EGFR inhibitors
TKI: intracellularly, erlotinib, gefitinib
MABs: extracellularly, cetuximab
HER2/neu inhibitors
TKI: lapatinib
MAb: trastuzumab
VEGF inhibitors
TKI: sunitinib, sorafenib
MABs: bevacizumab
