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86 Cards in this Set
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strategies for designing anti-neoplastic regimens
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start when tumor is small
use the maximum tolerated dose administer drug as frequently as possible repeat treatments in multiple cycles use combination therapy: drugs with different mechanisms and toxicities drugs susceptible to different mechanisms of resistance |
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log-kill hypothesis
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cytotoxic drugs act by first-order kinetics killing a constant proportion of a cell population
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cell cycle
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G1: synthesis of DNA precursors
S: DNA replication (synthesis) G2: synthesis of mitotic components M: mitosis G0: resting phase |
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alkylating agents
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form strong electrophile intermediates that covalently alkylate nucleophilic groups
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What does alkylation of DNA and proteins do?
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causes cell cycle arrest (non-specific phase), apoptosis
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What are the toxicities of Alkylating agents
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bone marrow, GI mucosa, CNS
myelosuprression |
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nucleophile
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forms a chemical bond with an electrophile by donating both electrons
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nitrogen mustards: drug class and names
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alkylating agents
mechlorethamine cyclophosphamide |
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nitrogen mustards mechanism and drug names
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mechlorethamine
cyclophosphamide bifunctional alkylating agents -cross-link DNA strands -cross-link DNA and protein -more cytotoxic than monofunctional agents non-specific cell cycle target |
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mechlorethamine: drug class and use
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alkylating agent
nitrogen mustard Hodgkin's disease most reactive agent, generally replaced with more stable agents |
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cyclophosphamide
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alkylating agent
nitrogen mustard most widely used alkylating agent selective for malignant tissues: normal tissue is protected by capacity to enzymatically degrade activated intermediates give with 2-mercaptoethanesulfonate (mesna/MESNEX) SE: metabolizes to acrolein (nephrotoxic, make sure adequate fluid intake), immunosuprresion, alopecia |
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nitrosoureas drugs:
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carmustine (BCNU)
streptozocin (streptozotocin) |
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Carmustine
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nitrosurea alkylating agent
highly lipophilic tx: malignant gliomas Hodgkins, non-hodgkins lymphoma, multiple myeloma SE: myelosuppression |
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streptozocin
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nitrosurea alkylating agent
targets pancreatic islet cell SE: hypoglycemia- insulin shock renal and hepatic toxicity |
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triazenes
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dacarbazine
methylating agent |
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methylhydrazines: drug
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procarbazine
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procarbazine: mechanism
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methylhydrazine
uses cytochrome P450 methylates DNA: inhibits DNA, RNA, protein synthesis monofunctional: produces chromosomal damage |
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platinum complexes
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cis-platinum (cisplatin)
carboplatin oxaliplatin |
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cisplatin/cis-platinum
carboplatin mechanism and use |
mechanism: reacts with nucleophilic sites on DNA (esp. N7 of guanine) and proteins
use: CMV carboplatin: much less toxic, major SE is myelosuppression |
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oxaliplatin
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alkylating platinum complex
MOST WIDELY USED FIRST LINE TREATMENT FOR ADVANCED COLORECTAL CANCER- COMBINED WITH 5FU AND LEUCOVORIN (FOLFOX) SE: peripheral neuropathy: dose limiting, reversible does not exhibit cross resistance with other platinum agents (cisplatin, carboplatin) |
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antimetabolites
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folic acid analogs
folate antagonist rescue agent pyrimidine analog purine analogs and related inhibitors |
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purine analogs and related inhibitors
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6 thiopurines
6 mercaptopurine 6 thioguanine fludarabine-5-phosphate |
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purine analogs and related inhibitors drug names and mechanism
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6-thioguanine (purine antagonist)
6-mercaptopurine (purine antagonist) fludarabine-5-phosphate (adenosine analog, inhibit DNA and RNA synthesis-> apoptosis) mechanism of mercaptopurine, thioguanine: inhibit purine synthesis 1 in 300 have a mutation that blocks the metabolism of 6MP, drug accumulates and can become fatal |
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folic acid analog drug name
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methotrexate
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methotrexate:
class mechanism use: SE |
folic acid analog
mechanism: inhibits dihydrofolate reductase, deplete tetrahydrofolate cofactors required for synthesis of purines, thymidylate use: curative for osteogenic sarcomas, choriocarcinomas (placental epithelium), breast cancer in post menopausal women with no tumor estrogen receptor expression SE: renal damage- hydrate toxicity prevented or reversed with leucovorin |
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folate antagonist rescue agent
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leucovorin
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pyrimidine analogs
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5- fluorouracil 5-FU
cytarabine (AraC) gemcitabine |
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5-fluorouracil
drug class mechanism treat |
pyrimidine analog
mechanism: uracil analog, decreases DNA synthesis most commonly used for COLORECTAL cancer |
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cytoarabine:
drug class mechanism |
drug class: pyrimidine analog
mechanism: cytosine deoxyriboside analog |
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gemcitabine
drug class mechanism |
pyrimidine analog
cytosine deoxyriboside analog |
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plant alkaloids
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vinca alkaloids
epipodophyllotoxins camptothecins taxanes |
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Vinca alkaloids
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plant alkaloids:
vinblastine vincristine |
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epipodophyllotoxins
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plant alkaloids
etoposide teniposide |
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camptothecins
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plant alkaloid
topotecan |
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taxanes
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plant alkaloid
paclitaxel |
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vincristine
vinblastine mechanism |
plant alkaloids
vinca alkaloids anti-mitotic drugs, M phase specific bind tubulin |
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vincristine: main treatment for
side effect |
childhood acute lymphoblastic leukemia
peripheral neuropathy |
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vinblastine main treatment for
SE |
curative therapy of metastatic testicular tumors in combination with bleomycin (antitumor antibiotics) and cisplatin (platinum complexes)
bone marrow suppression |
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etoposide
teniposide drug class mechanism |
plant alkaloid: epipodophyllotoxins
mechanism: inhibits topoisomerase 2: block DNA replication |
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topotecan
mechanism |
plant alkaloid
camptothecin bind to and inhibit activity of topoisomerase 1: single strand breaks bronzing of skin |
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paclitaxel
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plant alkaloid
Taxane mechanism: promotes microtubule polymerization and stabilization antimitotic- M phase specific metastatic ovarian and breast cancer |
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Anti tumor antibiotics
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actinomycin D
anthracyclines adriamycin (doxorubicin) bleomycin mitomycin |
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Antitumor antibiotics
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-mycin
actinomycin D anthracyclines Adriamycin (doxorubicin) bleomycin mitomycin |
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Actinomycin D (dactinomycin)
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antitumor antibiotic
binds DNA by intercalating between GC base pairs and blocks RNA synthesis and ultimately DNA synthesis one of the most potent antitumor agents known curative in wilm's kidney tumor and rhabdomyoasarcoma |
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adriamycin (doxorubicin)
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intercalate with DNA and binds to the backbone of DNA
blocks synthesis of DNA and RNA cardiotoxicity |
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bleomycin
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G2 phase specific: cells accumulate in G2
Binds DNA generates free radicals produces strand breaks inhibits ATP dependent DNA ligase, preventing DNA repair |
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mitomycin
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anti-tumor ABX
cross-links DNA, inhibits DNA synthesis used only if alternative are not effective |
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adrenocorticosteroids
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prednisone
hormonal agent |
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long acting gonadotrophin releasing hormone agonist
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leuprolide acetate
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progestin
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medroxyprogesterone
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anti-estrogen
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fulvestrant
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selective estrogen receptor modulator
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tamoxifen
raloxifene |
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aromatase inhibitor
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exemestane
anastrozole |
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anti-androgens
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flutamide
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classes of hormonal agents
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adrenocorticosteroids
long-acting gonadotropin releasing hormone agonists estrogens progestins anti-estrogens anti-androgens selective estrogen receptor modulators aromatase inhbitors |
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prednisone
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adrenocorticosteroid
metabolized to prednisolone which binds to glucocorticoid receptor regulates the transcription of specific proteins involved in metabolism and inflammatory response SE: cushing syndrome, immunosuppression |
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leuprolide acetate
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long acting GnRH agonist
prolonged exposure to long acting agonists downregulates GnRH receptor number-> suppresses gonadotropin release MOST COMMON TX FOR METASTATIC GONADAL STEROID-DEPENDANT PROSTATE CANCER |
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Fulvestrant
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anti-estrogen
high affinity estrogen receptor antagonist TX: hormone responsive metastatic breast cancer in post-menopausal women |
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Flutamide
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anti-androgen
androgen receptor antagonist- prostate cancer |
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Tamoxifen
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selective estrogen receptor modulator: acts as an estrogen receptor agonist in some tissues and an ER antagonist in other tissues
anti-estrogen on breast estrogen on endometrium-> increased risk of cancer |
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raloxifene
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second generation selective estrogen receptor modulator
acts anti-estrogen on breast postmenopausal osteoporosis prevention reduction of risk of breast cancer in high risk post-menopausal women neutral effect on endometrium |
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exemestane
anastrozole |
aromatase inhibitors
inhibit estrogen synthesis |
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enzymes
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L-asparaginase
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substituted ureas
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hydroxyurea
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differentiating agents
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tretinoin
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protein tyrosine kinase inhibitors
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imatinib mesylate
gefitinib |
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proteasome inhbitors
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bortezomib
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monoclonal antibodies
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trastuzamab
rituximab cetuximab bevacizumab |
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biological response modifiers
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interferon-alfa
interleukin 2 granulocyte colony stimulating factor granulocyte/macrophage colony stimulating factor |
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L-asparaginase
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enzyme
catalyzed the hydrolysis of circulating asparagine Tx: acute lymphocytic leukemia SE: hypersensitivity inhibition of protein synthesis |
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hydroxyurea
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substituted urea
inhibits ribonucleotide reductase-> decreased deoxynucleoside decreases DNA synthesis S phase specific high oral bioavailability |
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tretinoin (all-trans retinoid acid)
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regulates the transcription of genes that have retinoic acid inhibitors
induced differentiation- cells do not proliferate TX: acute promyelocytic leukemia SE: retionic acid syndrome, vit. A toxicity |
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imatinib mesylate
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protein tyrosine kinase inhibitor
remission in patients with chronic myelogenous leukemia |
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gefitinib
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inhibits EGFR tyrosine kinase, blocks signal transduction pathways required for cell proliferation and survival
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bortezomib
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proteosome inhibitor
reversible inhibitor of the 26S proteasome-> silences NK-kB (transcription factor that promotes cell survival) |
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trastuzumab
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monoclonal antibody
use in metastatic breast cancers where the HER2/neu gene is amplified Blocks HER2/neu gene is amplifeid |
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rituximab
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monoclonal antibody
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cetuximab
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monoclonal antibody
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bevacizumab
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monoclonal antibody
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interferon alfa
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immunomodulatory
anti-proliferative antiviral activity |
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interleukin-2
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induces a T-Cell response that is cytolytic for tumor cells
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granulocyte colony stimulating factor
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stimulate neutrophils
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granulocyte/macrophage colony-stimulating factor
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increases production of neutrophils and monocytes and stimulates migration and phagocytic and cytotoxic activities
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target synthesis phase of cell cycle
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epipodhyllotoxins (inhibit Topo2)
antimetabolites: folic acid analogs/folate antag. rescue agent/pyrimidine analogs purine analogs/related inhibitors (purine) |
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targets G2 phase
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bleomycin
epipodophyllotoxins |
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targets mitotic phase
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vinca alkaloids
taxol |
