Cancer III Flashcards
DNA Intercalating Agents
- often called anti-tumor antibiotics
- derived from various strains of soil microbe streotomyces
- bind to DNA through intercalation between specific bases
- cause DNA strand breaks
- block synthesis of DNA, RNA or both
- dactinomycin, antracyclines, bleomycin
dactinomycin
- intercalating
- actinomycin D
- first anti cancer antibiotic derived from streptomyces
- intercalates between G-C bp
- interferes with DNA dependent RNA pol, causing inhibition of DNA transcription
- also causes single strand breaks in DNA
- wilms tumor, rhabdomyosarcoma, ewings
- anorexia, nausea, vomiting
- hematopoietic suppression with pancytopenia
anthracyclines
intercalating
- daunorubucin, doxorubicin, epirubicin, idarubicin
- reduced to intermediates that donate electrons to oxygen to make superoxide
- superoxide reacts with itself to make h2o2, which is cleaved in presence iron to form an OH radical
- Oh radical cleaves DNA
- dose limiting cardiotoxicity
- dexrazoxane needed- iron chelating that blocks free radicals
- neutropenia
- stomatitis, alopecia
doxorubicin
- intercalates via OH (anthracycline)
- adriamycin
- broad clinical spectrum, one of most widely used
- used for sarcomas, breast and lung carcinomas, lymphomas
daunorubicin and idarubicin
- intercalating via OH (anthra)
- used in combo with AraC for AML
epirubicin
- intercalating anthra (OH)
- used in FEC for treatment of metastatic breast cancer
bleomycin
- DNA intercalating
- mixture of two peptides from streptomyces
- binds to DNA and induces single/double strand DNA breaks
- acts in G2 phase
- used as component of PEB combo regimen for trt of testicular carcinoma or as a component of AVBD for hodgkins
- also effective agains sq cell carcinomas
- dose related pulmonary tox (fibrosis)
- minimally myelosuppressive
- cutaneous tox- hyperpig, hyperkeratosis, erythema
MT inhibitors
-plant natural products
-bind to tubulin, interfere with MT function
-cause mitotic arrest
-M phase!
vinca alkaloids-vinblastine, vincristing
-taxanes- paclitaxel, docetaxel
vinca alkaloids
-MT inhib
-vinblastine
vincristine
-derived from periwinkle plant Vinca rosea
-bind to tubulin, prevent polymerization of tubulin into MT
taxanes
- MT inhib
- paclitaxel
- docetaxel
- derived from yew trees
- paclitaxel first from slow growing pacific yew
- docetaxel from needles of european yew
- bind to tubuling and prevent DEpolymerization of MT
vinblastine
vinca alk-MT inhib (pol)
- component of ABVD for hodgkins
- myelosuppression, nausea, vomiting
- resistance through amp of p glycoproteins and mutations in the cancer tubulins reduce binding of drugs to targets
vincristine
- vinca alk MT inhib (pol)
- glucocorticoids in trt of childhood ALL
- component of MOPP
- dose limiting neurotox-peripheral neuropathy
- relatively low tox in bone marrow
- amp of p glycoproteins and mutated tubulin
paclitaxel
taxane MT inhib (depol)
- metastatic breast, ovarian, lung, head and neck
- neutropenia, peripheral neuropathy
- hypersensitivity reactions
docetaxel
- taxane MT inhib (depol)
- met breast, ovarian, lung, head and neck
- hormone refractory prostate cancer
- neutropenia, peripheral neuropathy
- hypersensitivity reactions
topoisomerase inhibitors
- normally mediate DNA strand breakage and resealing during replication or transcription of DNA
- I breaks and reseals ss, II double strand
- inhibitors cause permanent DNA strand breaks by preventing resealing
- epipodophyllotoxins- etoposide, teniposide
- camptothecin analogs- irinotecan, topotecan
epipodophyllotoxins
top II inhib
- etoposide
- teniposide
camptothecin analogs
- top I inhib
- irinotecan, topotecan
etoposide
- epipodophyllotoxin
- topo II inhibitor
- broad clinical spectrum
- testicular carcinoma, lung cancer, non-hodgkins
- dose limiting myelosuppression
- oral mucositis
teniposide
- -epipodophyllotoxin
- top II inhib
- ALL
- dose limiting myelosuppression
- oral mucositis
irinotecan
- camptothecin analog, top I inhib
- advanced colorectal cancer, lung, ovarian, cervical, brain
- severe neutropenia and diarrhea
topotecan
- camptothecin analog, top I inhib
- ovarian and small cell lung cancer
- severe neutropenia and diarrhea
hormones and antagonists
- used for hormone dependent neoplasms
- lymphomas, leukemias
- breast
- prostate
hormones for lymphomas and leukemias
- glucocorticoids-prednisone/ dexamethasone
- cytotoxic effects on lymphocytes, inhibit mitosis in lymphocytes
- prednisone + vincristine produce remission in ALL
- prednisone also component of MOPP and CHOP for hodgkins and non-hodgkins
- dexamethasone to reduce edema following radiation of brain tumors
hormone therapy for breast cancer
- usually estrogen dependent and can be suppressed by admin of estrogen antagonists
- selective estrogen receptor modulators-tamoxifen
- selective estrogen receptor downregulators- fulvestrant
- aromatase inhib- aminoglutethamide, anastrozole, letrozole, exemestane
selective estrogen receptor modulators
- SERMs
- tamoxifen
- trt of ER positive early stage and metastatic breast cancer
- used for prevention in high risk women
- hot flushes, hair loss, nausea/vomiting
- weak agonist of ER in endometrium, increased risk of endometrial cancer and thromboembolism
selective estrogen receptor downregulators
- SERDs
- fulvestrant first FDA approved
- binds to ER with >100 fold higher affinity of tamoxifen and inhibits hormone receptor complex formation
- also reduces ER expression
- post menopausal women with ER pos metastatic breast cancer
aromatase inhibitors
- aminoglutethamide (1st gen- weak and lots of tox), anastrozole (3rd gen, potent and selective), letrozole, exemestane
- inhibit aromatase, which is necessary for estrogen synthesis
- profound estrogen deprivation in post menopausal women
anastrozole
- first line for ER pos in postmenopausal
- early stage and advanced
- potent and selective
- non steroidal reversible (with letrozole)
- exemestane is steroidal, competes with androstenedione
- have replaced tamoxifen
hormones for prostate cancer
- androgen deprivation therapy through surgical or medical castration is useful
- leuprolide and coserelin
- flutamide, bicalutamide
leuprolide, goserelin
- GnRH analogs
- bind to GnRH and inhibit FSH and LH, reduced testicular production of testosterone
- do not inhibit adrenal androgen syn
flutamide, bicalutamide
- non-steroidal androgen receptor blockers
- compete with natural hormone testosterone for binding with AR
hydroxyurea
- inhibits ribonucleotide reductase, no deoxyribonts
- trt of myeloproliferative neoplasms (polycythemia vera, essential thrombocytopenia
- sickle cell
all trans retinoic acid
- APL
- differentiation of promyelocytes
arsenic trioxide
-heavy metal toxin effective in relapsed APL
thalidomide
- approved for trt of multiple myeloma and MDS
- inhibits production of IL6, which is a GF for myeloma cells
- inhibits angiogenesis
interferon alpha
-hairy cell leukemia, CML, AIDs related kaposis
TKIs
- imatinib for CML
- gefitinib/erlotinib (EGFR inhib) for non small cell lung
monoclonal antibodies
- trastuzumab for her2 +
- cetuximab (against ErbB1) for metastatic colon cancer
multi drug resistance
- resistance to multiple drugs may occur due to increased expression of cell surface glycoproteins involved in drug efflux
- such drug transporters use ATP to drive drug molecules out of cancer cells
- veraparnil (Ca channel antagonist) inhibits these drug transporters
bleomycin tox
-pulm fibrosis
cisplatin tox
-nephro, oto, peripheral neuro
cyclophosphamide tox
hemorrhagic cystitis
anthracyclines (doxorubicin)
-cardio
methotrexate
-renal, hepato, bone marrow
paclitaxel
-peripheral neuro
vincristine
-neuro- peripheral
