Antineoplastics Flashcards
- antimetabolites
- topoisomerase II inhibitors
- microtubule poisons
- bleomycin
- all drugs are cell cycle ______
specific
- alkylating agents
- antitumor antibiotics
- topoisomerase I inhibitors
- all drugs are cell cycle _______
nonspecific
bleomycin causes?
pulmonary fibrosis
cyclophosphamide adverse effect
cystitis
anthracyclines (daunorubicin, doxorubicin) adverse effects
cardiotoxicity
cisplatin adverse effects
nephrotoxicity
cepaceitabine, pemetrexed effects
hand and foot syndrome
vincristine, docetaxel, paclitaxel adverse effects
neurotoxicity
irinotecan adverse effects
intestinal toxicity (diarrhea)
- tumor cells initially not sensitive to a given drug
- test by in vitro sensitivity by cell conolony assays or genotyping
primary resistance
- tumor cells develop resistance during drug therapy
- changes in permeability, amplification/alteration of targets, enhanced repair
secondary resistance
- MDR protein
- can export multiple classes of anti cancer drugs (antimetabolites, antibiotics, alkaloids)
p-glycoprotein
- impermeable to drug or pump drug out
- alternate targets for drug (glutathione)
- no apoptosis
- mechanism of restistance to what class?
alkylating agents
- bifunctional nitrogen mustard
- vesicant, caustic to skin and mucus membranes
- IV only (sQ causes necrosis), often in arterial supply to tumor
- half life minutes
- n/v, decreased blood counts w/ recovery in 3-6 wks
- use for Hodgkin’s (part of MOPP)
mechlorethamine
- oral or IV
- bioactivated by host metabolism (liver)
- adverse: n/v, bone marrow depression, alopecia
- sterile hemorrhagic cystitis
cyclophosphamide
_____ is the major cause of cyclophosphamide cystitis, protect by forced hydration and Mesna
acrolein
- activated non enzymatically
- lipid soluble, cross BBB
- Lymphomas and brain tumors
- IV or direct brain implant
- GI, myelosuppression
nitrosoureas (carmustine, lomustine, beadamustine)
- sugar molecule attached to nitrosourea structure
- malignant pancreatic insulinoma, malignant carcinoid
streptozocin
alkylating agent used for multiple myeloma and myeloablative therapy?
melphalan
alkylating agent used for CLL?
chlorambucil
alkylating agent used for CML? seldom used after imatinib, sulfur mustard not nitrogen
busulfan
- superficial papillary bladder cancer
- palliative for adenocarcinoma of breast or ovary
- controlling intracavity effusions caused by metastatic tumors
thiotepa
metastatic islet cell carcinoma of pancreas
streptozocin
- bifunctional platinating agent, cross links DNA
- blocks DNA synthesis
- IV, cleared in urine
- non toxic to bone marrow
- n/v (use ondansetron)
- renal toxicity, dose limiting
cisplatin
- causes more myelosuppression than cisplatin, less nausea and renal
- solid tumor treatment
carboplatin
- less renal than cisplatin, but neurotoxic
- advanced colorectal cancer
- solid tumors
oxaliplatin
- alkylating agent, also causes strand cission
- bioactivated, blocks DNA and RNA synthesis
- standard toxicities: n/v/bone marrow suppression
- strongly leukemogenic and teratogenic
procarbazine
- IV, converted to active methylating metabolite MTIC by CYP enzyme
- treat malignant melanoma, hodgkin’s
dacarbazine
- oral prodrug
- crosses BBB
- anaplastic astrocytoma, glioblastoma multiforme
temozolomide
- analogs of normal components that target the cells
- enters normal path then blocks
- folate analogs, purine and pyrimidine analogs
antimetabolites
- DHFR inhibitor, depletion of tetrhydrofolate shuts down biosynthetic paths
- greater accumulation in tumor cells
- blocks produciton of bases required for DNA synthesis
methotrexate
- oral, IV, intrathecal
- excreted in urine
- high dose followed by rescue with folinic acid
- anti folate effects
- resistance: aplified DHFR, decreased accumulation of polyglutamates
methotrexate
- oral, well toelrated, bone marrow depression only at high doses
- bioactivated by salvage path (HGPRT)
- blocks DNA and RNA synthesis, inhibits AMP and GMP, or incorporated into DNA altering function
- used for leukemias and lymphomas
- resistance from decrease in hgprt activity, or increase in alk phos
purine analogs
- active metabolite, inactivates thymidylate synthase
- folinic acid required for inactivation of thymidylate synthase
- treat many carcinomas
- bone marrow toxicity, GI
5-flurouracil
- cytosine analog, chain terminator
- CCS: active during S phase
- treat AML, ALL, CLL, high grade lymphomas
cytarabine
- inhibits tubulin polymerization, disrupts mitotic spindles
- metaphase arrest
- IV admin
- biliary excretion
vinca alkaloids (vincristine, vinblastine)
-vinca alkaloid that causes alopecia, bone marrow depression
vinblastine
-vinca alkaloid that causes peripheral neuropathy
vincristine
- affects microtubules by stabilization
- blocks progression through M phase
- effective in solid tumors
- IV in cremaphor –> hypersensitivity
- acute hypersensitivity, nausea
- delayed bone marrow suppression, neuropathy
paclitaxel, docetaxel
- topoisomerase II inhibitors, double strand breaks, DNa degradation
- induces apoptosis
- oral and IV
- bone marrow suppression, alopecia
etoposide, teniposide
etoposide and teniposide arrest cell in _____ stage
S-G2
- topoisomerase I inhibitors (ss DNA breaks)
- myelosuppressive
- dose limiting toxicity is severe diarrhea
topotecan, irinotecan
______ in combo with 5-FU and leucovorin is first line for metastatic colorectal cancer
irinotecan
prodrug metabolized to SN-38, metabolized by UGT1A1 so do genetic testing
irinotecan
- block access to/function of DNA or RNA
- all IV
- unique toxicities
- most produced by microbes
antitumor antibiotics
- intercalate into DNA
- blocks topoisomerase II, cause strand breaks
- generate free radicals
- IV, hepatic clearance
anthracyclines (dox/daunorubicin)
- bone marrow suppression, GI distress, severe alopecia
- signature adverse is cardiotoxicity (arryhtmias, cardiomyopathy, CHF)
- free radicals minimized by dexrazoxance (iron chelator)
anthracyclines (doxo/daunorubicin)
- mix of glycopeptides
- binds DNA, generates free radicals –> strand breaks, active in G2
- hypersensitivity, cutaneous rxns
- pulm toxicity, fibrosis
bleomycin
- effective against solid tumors
- activation favored by hypoxia, alkylates DNA
- given IV or by bladder instillation
- very toxic: severe bone marrow suppression, GI, renal
mitomycin C (antitumor antibiotic)
- intercalates, blocks RNA and DNA synthesis
- radiation recall: inflammation at sites of prior radiaiton
dactinomycin (actinomycin D)
- depletes serum asparagine needed by some tumors
- parenteral
- hypersensitivity
- use in ALL
asparaginase
- inhibits ribonucleotide reductase
- oral therapy for leukemias, some head and neck
- mucositis, rash, bone marrow suppression
hydroxyurea
- monoclonal antibody, blocks CD20 B cell antigen
- IV, half life 22 days
- for B cell lymphomas, CLL, non hodgkins
- hypogammaglobulinemia, autoimmune disorders
rituximab
- suppress proliferation of immune cells (leukocytes, lymphocytes)
- oral
- delayed: fluid retention, immunosuppression, diabetes
prednisone, hydrocortisone
- block conversion of androgens to estrogens
- specific for estrogen production
selective aromatase inhibitors
- azole, similar to antifungals
- more effective against peripheral aromatase
- for ER+ primary and metastatic breast cancer
anastrazole, letrozole
- steroidal irreversible aromatase inhibitor
- no cross resistance w/ azoles
- fatigue, hot flashes
exemestane
- competing ligands for estrogen receptor
- more effective in post menopausal women
SERMs
- ER antagonist in breast, ER agonist in endometrium
- converted by CYP2D6
- chemopreventive for breast cancer
- ER+ primary and metastatic
tamoxifen, toremifine
- ER antagonist in breast, ER agonist in bone
- chemoprevention for breast cancer, treatment and prevention of osteoporosis
- hot flashes, vaginal bleeding
raloxifene
- use with leuprolide and/or radiation for prostate cancer
- hot flashes, transient hepatic effects
flutamide, bicalutamide
- cytokine produced by WBCs
- parenteral
- alters gene expression, antiviral and immunomodulatory
- used against hematologic malignancies, metastatic melanoma, renal cell carcinoma
- fever and chills, anorexia, weakness
interferon- alpha
- monoclonal antibody against Her2neu oncogene (epidermal growth factor)
- receptor amplified in 25% of breast cancers
- IV
- hypersensitivity, cardiomyopathy
trastuzamab (herceptin)
- inhibits Bcr-Abl and c-kit (GI stromal tumors) tyrosine kinases
- used in CML
- any hematologic malignancy with Philadelphia chromosome
- myelosuppressive
- edema, fluid retention, hepatotoxic
imatinib (gleevec)
- newer receptor tyrosine kinase inhibitors, broad spectrum
- use in imatinib resistance
dastinib, nilotinib
- inhibits bruton’s tyrosine kinase, essential for B cell receptor signaling
- oral
- metabolized by CYP3A4
- for mantle cell lymphoma, refractory CLL
- adverse: GI, thrombocytopenia, neutropenia, infections, fatigue
ibrutinib
- PI3K inhibitor
- metabolized by aldehyde oxidase and CYP3A4 (Strong inhibitor)
- relapsed CLL and SLL, relapsed follicular B cell lymphoma
- hepatotox, diarrhea, colitis, pneumonitis, intestinal perf
idelalisib
- inhibits 26S proteasome, disrupts signal cascades, apoptosis
- multiple myeloma, mantle cell lymphoma
- causes thrombocytopenia, fatigue, peripheral neuropathy
- hypotension upon infusion
bortezimib
- monotherapy or w/ anthracycline or arsenic for APL
- binds to RAR-alpha receptor, promotes differentiation
- promotes degradation of PML RAR-alpha fusion protein
- resistance through enhanced clearance (CyP25A1) or loss of expresion of fusion gene
all trans retinoic acid
- inhibits thioredoxin reductase, enhancing oxidative stress
- modification and degradation of APL fusion protein
- cytotoxic, promotes differentiation
arsenic trioxide (As2O3)
- thalidomide derivative
- CLL, multiple myeloma
- lacks sedative effects and teratogenic of thalidomide
- inhibits rituximab
lenalidomide
