Antineoplastics Flashcards
Imatinib
- t(9,22) Philadelphia chromosome
- lipophilic, metabolized by CYP450 (CYP3A4)
- binds inactive kinase receptor, inhibits ATP binding site
- causes: N,V,D,skin rxns,hepatotoxicity,hypertension,myelosuppression, edema,CH
- use: GI strongly tumors
Gefitinib/Erlotinib
- deletions in exon 19, L858R
- blocks EGFR-ERB1, tyrosine kinase inhibitor
- EGFR has 4 family receptors (ERbB1-4) which may compensate for one
- causes:rash,diarrhea, hypertension,hepatotoxicity,GI perforation,lung diseas
- use: NSCLC
Trastuzumab (Herceptin)
- EGFR HER2 inhibitor, blocks dimerization
- mediates receptor blockade, receptor internalization and apoptosis
- causes:N,V,D,rigors,cardiac dys,CHF,hypotension,edema
- use: breast cancer with taxol
Bevacizumab
- anti-VEGF, inhibits angiogenesis
- uses:colon cancer,vasculopathy of eyes
Ipilimumab
- anti CTLA4(cytotoxic T lymphocyte associated protein 4)
- CTLA4 downregulates immune system
- use: melanoma, NSCLC
Pembrolizumab, Nivolumab
- against PD1 (programmed death receptor 1)
- expressed on subset of NK cells
- effective in pts with biomarker,mismatch repair deficiency
- use:melanoma, NSCLC,Hodgkins lymphoma
Thalidomide
- inhibits VEGF and bFGF
- arrests myeloma cells at G1, decrease of IL1,IL6,lessen cell adhesion, disruption of BCL2 antiapoptosis, increase IL2 and NK activity
- teratogenic, peripheral neuropathy
Bortezomib
- inhibits ubiquitin-proteasome pathway
- disregulates protein turnover in cell and NK inflammatory pathways
- sensitizes cells to apoptosis via ER stress and unfolded protein response
- VERY toxic, toxic dose=therapeutic dose
- causes:peripheral neuropathy, hypotension,GI dys,myelosuppression
What are the Classical Toxicities?
Bone marrow suppression, ulcers of oral/GI mucosa,alopecia,impaired wound healing, crystalluria
Mechlorethamine - Alkylating agent
- binds directly to DNA
- spontaneous activation to reactive carbonium ions
- given by IV near tumor site
- classical toxicity, bone marrow suppression is limiting
Cyclophosphamide - Alkylating agent
- bind directly to DNA
- prodrug activated by CYP450
- given orally, wide distribution, metabolities/active drug in urine
- causes: classical toxicity, myocarditis, hemorrhagic cystitis
- use: hematogenous tumors and solid tumors
Allopurinol
- reduces hyperuricemia and crystalluria associated with massive cell death and purine release
- helps with classical toxicity from drugs
MOPP and COP
M-mechlorethamine, O-Oncovin(vincristine), procarbizine, prednisone
C-cyclophosphamide, Oncovin, prednisone
Cisplatin - platinum analogs
- bind directly to DNA
- crosslinkers, only cis is active, fixed positive charge
- exchange Cl group for electrons in O,N,P, and DNA
- strongly bind tissue, eliminated unchanged in urine
- causes:nephrotoxicity,N,V,neuropathy,ototoxicity
Actinomycin D - antibiotics
- bind directly to DNA
- generates free radicals to tear DNA apart, specific bind deoxyguanine
- IV, multiple half lives, excreted unchanged in urine and bile
- causes: classical toxicity
- use: carcinomas, Wilm’s tumor, Kaposi’s sarcoma, curative in testicular
Adriamycin (Doxorubicin) - antibiotics
- bind directly to DNA
- intercalated quionone redox center binds Fe2+ oxidizes to Fe3+
- passes electron to oxygen to make free radicals
- IV,wide distribution except CNS,metabolized by liver,excreted in bile
- classic toxicity and cardiotoxicity, free radicals have no buffer in heart
- solid and hematogenous tumors
- Idarubicin and epirubicin
Bleomycin - antibiotics
- glycopeptides intercalate and make free radicals by binding iron
- NO bone marrow suppression
- cause: skin lesions,hyperpigmentation,pulmonary fibrosis
- IV or IM
- use: lymphoma,germ cell cancers, head and neck cancer
- caution when giving to smokers
Etoposide (Teniposide) - topoisomerase inhibitors
- bind directly to DNA/topoisomerase II
- cause dsDNA breaks
- renal elimination, some hepatic and biliary excretion
- use: lymphomas, lung, gastric cancer
- cause:N,V,bone marrow suppression, hepatic toxicity,increased leukemia
- resistance occurs by MDR1 gene, ABC transporter P170 pumps drug out
Methotrexate - antimetabolites
- do not directly bind DNA
- depletes folic acid, unable to make dTMP from dUMP
- DNA synthesis fails and causes apoptosis
- excreted unchanged in urine, NSAIDs compete/ reduce polyglutamation
- classic toxicity, hepatotoxicity, nephrotoxicity
- use: choriocarcinoma,lymphoma,sarcoma,leukemia
6-Mercaptopurine - purine analog
- phosphorylated via salvage pathway
- inhibits enzymes for ATP/GTP synthesis, disturb DNA structure
- metabolized by xanthine oxidase/thiopurine methyltransferase
- unchanged in urine
- classic toxicity, hepatotoxicity, must decrease allopurinol dose
- use: childhood cancers, leukemia, lymphoma, Hodgkins
5-Fluorouracil - pyramidine analogs
- phosphorylated via salvage pathway to 5FdUMP
- parental, hepatic metabolism by DPD, genotyping to prevent toxicity
- classical toxicity, ataxia, GI, skin
- capacitabine is prodrug
Vinblastine, Vincristine - mitotic spindle inhibitors
- bind tubulin to disaggregate mitotic spindles - mitotic arrest
- widely followed by CCS agents
- IV, distribute widely except CNS
- metabolized by CYP3A4
- use: lymphoma, sarcoma, solid tumors
- cause: myelosuppression, peripheral neuropathy
Paclitaxel (Taxol) - mitotic spindle inhibitor
- mitotic arrest by binding tubulin, stabilizes microtubules
- metabolized by CYP3A4, resistance from MDR1 gene
- use: breast, ovarian, head/neck, lung, bladder, prostate, melanoma
- cause:myelosuppression, peripheral neuropathy,cardiac block, arrhythmia
Docetaxel
- mitotic spindle inhibitors
- NSCLC, breast, head/neck,gastric,prostate
Leuprolide - GnRH Agonist
- chronic treatment causes decrease in GnRH receptor
- causes decrease in LH and FSH, decrease in androgen/estrogen at first
Degarelix/Cetrorelix - GnRH antagonist
- cause decrease in LH and FSH
- decrease in androgens and estrogen, no surge
Estradiol/ tamoxifen
Estrogen agonist/antagonist
Danazol/flatamide
-androgen agonist/antagonist
Vorozole, Letrozole - aromatase inhibitors
- better ER(+) tumor shrinkage, better relapse prevention
- used for premenopausal women with ovarian suppression
Retinoic Acid
- APL associated w/ t(15,17) and broken RAR-alpha
- effective treatment with increase levels of RA
- increase RA: stimulate broken RAR by releasing corepressors from receptor
Cytotoxic drugs that interfere with DNA replication by cross linking DNA strands and DNA strand breaking are classified as _______________.
Alkylating agents
-Mechlorethamine and Cyclophosphamide
