Anti-neoplastic Drugs Flashcards
cell cycle non-specific drugs
nonspecific cytotoxicity; kill cells in any stage of cell cycle even G0; kill normal and neoplastic cells equally. e.g alkylating agents
cell cycle specific phase specific drugs
most active at specific phase of cell cycle; some selectivity of action (more cytotxic for neoplastic cells than normal cells); given by continuous infusion or frequent small doses
G1 phase specific agents
prednisone
S phase specific agents
cytarabine, fluorouracil, methotrexate, mercaptopurine, hydroxyurea
G2 phase specific agents
bleomycin, etoposide, paclitaxel
M phase specific agents
vinblastine, vincristine
Cell cycle specific, phase non-specific
prefer killing proliferating neoplastic cells but in any phase; given in large doses to spare normal cells in G0; drawback = solid tumors often have lots of cells in G0
examples of Cell cycle specific, phase non-specific
cyclophosphamide, cisplatin, doxorubicin
alkylating agents
introduce alkyl groups into DNA, RNA and/or proteins; causes DNA crosslinks and strand breaks. cell cycle nonspecific. SE: hematopoiesis suppression, damage to intestinal mucosa, N/V, alopecia
classes of alkylating agents
nitrogen mustards (mechlorethamine, cyclophosphamide), nitrosoureas (carmustine),
mechlorethamine
nitrogen mustard. alkylating agent, produces DNA crosslinks. used for hodgkin’s and non-hodgkin’s lymphoma
cyclophosphamide
oral or parenteral, cycle-specific phase-nonspecific. activation by liver P450 to phosphoramide mustard–> toxic side product acrolein (Mesna!), broad spectrum of activity. SE: sterile hemorrhagic cystitis
carmustine
IV. highly lipophilic = good for brain tumors
Antimetabolites
analogs of compounds required for intermediary metabolism, many are phase-specific (often S), best with rapid cell proliferation
methotrexate
folate analog. binds DHFR prevents THF formation. in high doses follow with Leucovorin rescue. binds to serum albumin (CI w drugs that will displace it from albumin). SE: bone marrow suppression, renal tubular necrosis. TX: ALL, choriocarcinoma
pyrimidine analogs
fluorouracil, cytarabine
fluorouracil
activated in cells to FUTP (inhibits RNA synth), FdUMP (interferes w thymidylate synthetase & DNA synth). S-phase specific. TX: IV for GI cancers, topical for basal cell carcinomas. SE: N, anorexia, diarrhea, delayed myelosuppression
cytarabine
cytidine analog, competes for phosphorylation to dCTP, competes with dCTP for incorporation –> chain termination. s-phase specific. SE: myelosuppression & neurotoxicity. Tx: acute leukemias
mercaptopurine
purine analog, converted to ribonucleotide, inhibits RNA and DNA synthesis. S phase specific. Tx: acute leukemia. SE: bone marrow depression, N/V, anorexia, jaundice
hydroxyurea
miscellaneous antimetabolie, inhibits ribonucleotide reductase to block DNA synth. arrests cells at G1/S interface. tx: granuclocytic leukemia, head & neck cancer. SE: hematopoietic depression, GI disturbances
vinca alkaloids
bind to tubulin, inhibit proper formation of microtubules and mitotic spindle, arrests cells in metaphase. M phase specific. ex: vinblastine, vincristine
vinblastine
tx: hodgkin’s and non-hodgkin’s lymphoma, breast cancer. SE: strongly myelosuppressive, epithelial ulcerations
vincristine
tx: ALL, hodgkin’s and non-hodgkin’s, Wilm’s, neuroblastoma, rhabdomyosarcoma. SE: alopecia, neuromuscular abnormalities (peripheral neuropathy), less BM suppression
taxanes
block late in G2 phase (G2/M interface). enhance assembly and stability of microtubules by binding to tubulin’s beta-subunit.
paclitaxel
tx: refractory ovarian cancer, breast. SE: dose-limiting leukopenia, peripheral neuropathy, myalgia/arthralgia. SE: dose-limiting leukopenia, peripheral neuropathy, myalgia/arthralgia
antitumor antibiotics
doxorubicin, bleomycin
doxorubicin
intercalates btwn DNA base paird, distorts DNA helix. causes lipid peroxidation and free radical damage. binds to DNA and topoisomerase II. cycle-specific, phase non-specific. SE: CARDIOMYOPATHY, BM depression, alopecia, GI probs.
bleomycin
glycopeptide mixtures bind to DNA, cause oxidative-like damage to DNA, DNA strand breaks. phase specific for G2 (and M). SE: dose-related pulmonary toxicity, vesiculation of skin/skin hyperpigmentation, minimal myelosuppression and immunosuppression
epipodophyllotoxins
etoposide
etoposide
stabilizes DNA topo II causing dsDNA breaks. late G2 (also late S). SE: leukopenia, N/V, diarrhea, alopecia
biological response modifiers (BRM)
agents that affect patient’s biological response to neoplasm beneficially. includes agents that act indirectly to mediate antitumor effects or that act directly on tumor cells
filgrastim
G-CSF, stimulates granulocyte (PMN) production by marrow. given after myelosuppressive agents. SE: bone pain
trastuzumab
MAB that binds to HER2 receptor, used in cancers that overexpress HER2. SE: cardiomyopathy, hypersensitivity, infusion reactions
cisplatin
platinum coordination complex, activated species causes DNA crosslinks. promotes apoptosis. cycle-specific phase-nonspecific (sometimes S phase specific). wide antitumor spectrum. SE: nephrotoxicity, ototoxic, peripheral neuropathy, electrolyte disturbances, N/V
procarbazine
activated in vivo to methylating agent that causes chromosomal damage. G1 & S phase. TX: Hodgkin’s. SE: myelosuppression, N/V
hormones and antagonists
some tumors are steroid hormone-dependent. can do steroid hormone receptor assay to ID patients for endocrine therapy
prednisone
adrenocorticosteroid. binds to steroid receptors, depress RNA synth of growth-related genes, induces nucleases that modulate cell lysis. arrests cells at G1. anti-emetic, palliative therapy. limited myelosuppression but long term use bad. ALL, CLL, hodgkin’s & non-hodgkin’s
tamoxifen
estrogen receptor antagonist. antiestrogen, blocks ER alpha, activated by CYP2D6. TX: breast cancer, prophylaxis if high risk. SE: hot flashes, fatigue, N/V, bone/musculoskeletal pain
letrozole
aromatase inhibitor. inhibits androgen to estrogen conversion in all tissues. 1st line for breast cancer in post-menopausal women. SE: bone pain, musculoskeletal pain, fatigue
leuprolide
synthetic peptide analog of GnRH. initial testosterone surge followed by desensitized GnRH signaling, inhibition of LH/FSH secretion and drop in testosterone synth to castration level. Tx: prostate. SE: hot flash, impotence
flutamide
antiandrogen, blocks androgen receptors. tx: metastatic prostate cancer. SE: gynecomastia, diarrhea, hepatotoxicity.
reasons for resistance
resting cells. toxicity limits dose. spontaneous mutations. clinical resistance. selection & overgrowth (small fraction of cells in tumor resist & keep growing). MDR (drug efflux pumps)
strategies to circumvent resistance
increase dose. multi-drug regimens. co-administer agents that defeat resistance. give drugs with different metabolism/mech/both. recruit cells out of resting phase.
advantages to combo therapy
maximal cell kill within range of tolerable toxicity. broader range of coverage for de novo resistance. prevent or slow new resistance development.
principles of combination chemotherapy
use multiple agents likely to be effective vs various cell types. include drugs active as single agents. use agents w non-overlapping toxicities. use each drug at its optimal dose and schedule. give combos at consistent intervals. use drugs with different mechanisms of action.
sequential blockade
simultaneous action of two inhibitors acting on different enzymes of a linear metabolic pathway. ex: hydroxyurea + cytarabine; methotrexate + fluorouracil
concurrent inhibition
inhibitors block two separate paths leading to same end product
complementary inhibition
one inhibitor affects function of end product, other affects synthesis of that end product. ex: cytarabine + doxorubicin
rescue
rescue patient’s normal cells from the treatment. ex: leucovorin after MTX; autologous BM transplant
synchronization
tumor cells are synchronized to one phase for max effect from agent specific for that phase
recruitment
mobilize slowly- or non-proliferating cells into more rapid proliferation. initiate therapy w cell cycle-nonspecific drugs to reduce tumor bulk and recruit non-dividing cells into active DNA synthesis, follow w cycle-specific agents
