Antineoplastics and angiogenesis Flashcards
What are the rationale for anti-neoplastic drugs?
kill all tumor cells
suppress growth of tumor cells but not normal cells
improve ability of normal cells
Cancer stem cells are what?
small compartment of tumor often quiescent resistant to chemo and radiation can regenerate tumor one mechanism for drug resistance
At what size is a tumor visible on X-ray?
at 1 cm in diameter
When is a tumor first palpiable?
at 1 gram; when first become symptomatic
What type of kinetics does killing tumor follow?
first-order kinetics; so a constant dose of drug kills a constant fraction of tumor cells
Tumor size predicts what with respect to chemotherapy use?
not hte dose but duration of treatment
What must the chemotherapy regimen must be like to be curative?
have a 2-4 log kill efficiency and be repeated 4-12 times
Class II drugs target what type of tumor/cell?
target cells in specific stage of cell cycle
What do class III drugs target what type of tumor/cell?
targets cells in cell cycle relatively specific for cancer cells
What do class I drugs target?
target and kill all cells regardless of what sage they are at
What are targets-target therapies for antineoplastics?
targeting molecular targets taht are more specific for the cancer cells
What is angiogenesis?
extension of capillaries or blood vessels from existing blood supplies
What is vasculogensis?
formation of capillaries or blood vessels independently of old blood vessels and eventually join
What is the difference between vessels in tumor vs normal vessels?
tumor vessels lack smooth muscle all the way around them; and much more chaotic, holes used for mestasis
Why is it difficult for drugs to enter tumor?
itnratumor pressure due to damaged lymphatic vessels
What is the role of VEGF in permeability of vessels?
50,000 times more potent than histamine
What is NOTCH?
when it is cleaved and enters nucleus it is important in early angiogenisis by transcription increase
What are the benefits of anti-angiogenic therapy?
target genetically stable population
naturally occuring-high tolerance low side effects
ease accessibility
**this is the ideal
What is tumor doubling timea function of?
cell cycle time
growth faction
cell loss
What are are the four principles of tumor growth curve?
tumor mass generally first detectable at 10^9 cells
as a tumor grwos more cells enter G0
tumor cells are generally mores sensitivie to chemo agents during early growth periods
a palable tumor is large enought to have metastasized
What are the four stages of tumor growht?
I: tumor contained in organ of orgin
II: tumor metastasized regionally but is totally removable
III: metastasized regionally but no longer totally removable
IV: tumor is metastasized beyond local area
What log-kill rate is needed to double the expected lifespan of a patient?
2-4 log-kill
What is the total-kill concept?
one surviving cell can regenerate the tumor
the lifespan of the host is inversely related to the number of cells that survive therapeutic measures
What are two antineoplastic drugs that are class I?
non-specific cytotoxicity:
mechlorethamine
carmustine
What drug is a class II that focuses on cells in the G1 phase?
prednisone
What drugs are pyrimidine analogs that kill cells in the S phase greatest activity, class II?
Cytarabine, fluorouracil
What drug is an antimetabolite that is a folic acid analog that kills cells in the S phase? Class II
methotrexate
What drug is an antimetabolite, purine analog, class II, S phase ?
mercaptopurine
What drug is a class II, substituted urea, kill cells S phase?
hydroxyurea
What drugs are antibiotics, that are class II drugs, G 2 phase?
bleomycin, etoposide
What are the taxane, G2 phase, Class II?
Paclitaxel
What drug is Class II, m phase focused, a mitotic nhibitor?
vinblastine, vincristine
What drug is a class III alkylating agent?
cyclophosphamide
What drug is a miscellaneous metal salt, class III drug?
cisplatin
What drug is an antibitoic, class III drug?
doxorubicin
What is the dosing frequency for one cycle of treatment of class I agents?
given as a single dose for each cycle of therapy?
What is the dosing frequency for one cycle of treatment of class III agents?
given as a single dose for each cycle of therapy?
What is the dosing frequency for one cycle of treatment of class II agents?
given by continuous infusion or frequent small doses
What are the optimal intervals for cycles of treatments?
optimal intervals are those which deliver the next cycle of treatment when there is the greatest difference between recovery of normal tissue and recovery of tumor
What are the toxic effects of the alkylating agen mechlorethamine?
nausea vommiting, myelosuppression
What is the mechanism of action of alkylating agents as anti-neoplastic rugs?
introduce alkylgroups into DNA
cause DNA crosslinks, strandbreaks
What are the toxic effects of cyclophosphamide, an alkylating agen?
nasuea and vomitting
limited myelosuppression
alopecia
What are the toxic effects of carmustine?
nasuea and vommitting
delayed myelo suppression
What is mechlorethamine used to treat?
hodgkin’s and non-hodgkins lymphoma*
breast, lung and ovarian
What is cyclophosphamide used to treat?
very broad spectrum, mostly widely used Hodgkins and non-hodgkins lymphoma multiple myeloma neuroblastoma leukemias carcinoma of endometrium, breast lung
What is a unique side effect of cyclophosphamide?
may cause sterile hemorrhagic cytitis
What are the properties of carmustine?
alkylating agent, extensively metabolized in liver
highly lipophilic, rapidly crosses blood brain barreir
What is carmustine used to treat?
treatment of brain tumors, multiple myeloma, melanoma
What is the mechanism of action of methotrexate?
metabolized to polyglutamates which binds to dihydrofoloate reductase and prevent formation of tetrahydrofolate
What does methotrexate bind to?
serum albumin
What are the toxicities associated with methotrexate?
intestinal epithelium, bone marrow suppression
renal tubular necrosis
What is methotrexate used to treat?
acute lymphocytic leukemia; choriocarcinoma
What si teh mechanism of action of fluorouracil?
activated in cells to FUTP which inhbiits RNA synthesis and FdUMP whihc interferes with DNA synthesis
What is flurouracil used to treat?
carcinoma of the stomach, colon, pancreas, ovary, head and neck, breast, bladder
topical cream for basal cell carcinoma
What is the toxicity of fluorouracil?
nausea, anorexia, diarrhea, delayed myelosuppression
What is the mechanism of action of cytarabine?
cytidine analog
competes with cytidine for all 3 phosphorylation steps to dCTP
cytarabine tri-phosphate competes with dCTP for incorporation into DNA and causes DNA chain termination
What is the toxicity of cytarabine?
marked myelosuppression and neurotoxicity
What is cytarabine used to treat?
acute leukemia
What is the mechanism of mercaptopurine?
purine analog that is converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
What is mercaptopurine used to treat?
acute leukemia and chronic granulocytic leukemia
What is mercaptopurine toxicity?
gradual bone marrow depression vomiting nausea anorexia jaundice
What is the mechanism of action of hydroxyurea?
substituted urea that inhbiits ribonucleotide reductase blocking DNA synthesis; arrest at G1 to S pahse
What is hydroxyurea used to treat?
granulocytic leukemia, head and neck cancer
What is the toxicity associated with hydroxyurea?
hematopoietic depression, GI disturbances
What are the mechanism of action of vina alkaloids?
binds to tubuline, inhibiting proper formation of microtubules and miotic spindle, arresting cellls in metaphase
M phase-specific
What is Vinblastine used to treat?
hodgkins and non-hodgkins lymphoma
breast cancer
What is vinblastine toxicity?
strongly myelosuppressive
epithelial uclerations
neurological disturbance and bronchospasm
What is vincristine used to treat?
acute lymphocytic leukemia, hodgkins and non-hodgkins lymphomas, wilms tumor, neuroblastoma and rhabdomyosarcoma
What is the toxicity of vincristine?
alopecia
neuromuscular abnoramlities (peripheral neuropathy incl)
significantly less bone marrow suppression than vinblastine
What is the mechanism of action of taxanes?
blocks late in G2 phase; enhances assembly and stability of microtubules by binding to Beta0subunit of tubulin
What is paclitaxel usedd to treat?
refactory ovarian cancer; breat cancer
What is toxicity associated with Paclitaxel?
dose-limiting leukopenia, peripheral neuropathy, myalgia/arthalgia
What is the doxorubicin mechanism of action?
prevents DNA and RNA synthesis by intercalating between DNA base pairs, dostorting DNA helix
causes lipid peroxidation and free radical generation
binds to DNA and topo II
What is the Doxorubicin used to treat?
Hodgkin’s and non-hodgkin’s lymphoma, breast, ovary, small cell lung and other cancers
What toxicity is assoicated with doxorubicin?
cardiomyopathy
bone marrow depression, alopecia, GI disturbance
What is the mechanism of bleomycin?
a mixture of glycopeptides that bind to DNA
causes oxidative-like damage to DNA which leads to DNA strand breaks
phase specific for G2 and M
What is bleomycin used to treat?
germ cell tumors of testes and ovaries
head, neck, lung, lymphomas
What toxicitiy is associated with Bleomycin?
dose-related pulmonary toxicity
vesiculation of the skin, skin hyperpigmentation
minimal myelosuppression adn immunosuppresion
What is the mechanism of action fo Etoposide?
stabilizes DNA topo II complexes resulting in double strand DNA breaks
maximal effect in late G2 phase
What is used to treat with etoposide?
lymphomas, acute nonlymphocytic leukemia, small cell carcioma of lung, testicular tumor
What is the mechanism of Filgastrim?
stimulates granulocyte production by marow
What is Filgastrim used for?
given after myelosuppressive agent to speed neutrophil recovery;
bone pain major side effect
What is the mechanism of Trastuuzumab?
humanized monoclonal antibody that binds to HER2 receptor
Wha is trastuzumab used to treat?
breast cancer that overezpress HER2
What is the toxicity of Trastuzumab?
cardiomyopathy
hypersensitivity
infusion reacctions
What is the mechansim of cisplatin?
platinum coordination complex, hydrolysis leads to an activated species which causes DNA crosslinks, also promotes apoptosis
What is cisplatin used to treat?
wide antitumor spectrum, testis of cancer, ovary, head, neck bladder, esophoagus small cell lung
What is the toxicity associated with cisplatin?
nephrotoxicity ototoxicity peripheral neuropathy electrolyte disturbance nausea, vomitting, myelosuppression
What is procarbazine mechanism of action?
poorly understood, but activated in vivo to a methylating agent which causes chromsomal damage
What is procarbazine used to treat?
hodgkins
What is the toxicity associated with procarbazine?
myelosuppression, nausea, vomitting
What is the mechanism of action of tamoxifen?
nonsteroidal antiestrogen that blocks estrogen receptors thereby reducing tumor cell renewal
What is tamoxifen activatedd by?
CYP2D6
What is tamoxifen used for?
ajuvant therapy in post-menopausal breast cancer
pre-menopausal metastic breast cancer
treatment of certain endometrail and ovarian cancers
breast cancer prophylaxis***
What is tamoxifen toxicity?
hot flashes, fatigue, nausea, bone and other musculoskeletal pain
What is letrozole mechanism of action?
non-steroidal aromataase inhibitor, inhibitis conversion of androgens to estrogens
What is this treatment for letrozole?
breast carcinoma in post menopausal women
What are the side effects of letrozole?
bone paina nd other musculoskeletal pain, hot flashes, nausea, fatigue
What is the mechanism of action of leuprolide?
synthetic peptide analog oof gonadotropin-releasing horomone (GnRH)
after 2-4 weeks it desensitizes GnRH signaling inhibiting LH/FSH secretion decreasing testosterone synthesis to castration levels
What is leuprolide used to treat?
advanced horomonally rsponsive prostate cancer
What is leuprolide toxicity?
hot flashes, impotence
What is the mechanism of action of Flutamide?
potent nosteroidal antiandrogen that blocks androgen receptors
What is flutamide used to treat?
metastatic prostate cancer, often with GnRH analog
What is the toxicity of flutamide?
gynecomastia, diarrhea, hepatotoxicity
What is the reason for resistance to chemotherapy?
resting cells
dose limited by toxic effects on sensitive tissues
spontaneous mutations
clinical resistance
selectiona nd overgrwoth-major cause of chemotherapic failure
What is multi-drug resistance medaited by?
ATP-dependent drug efflux pumps
pump out a variety of drugs from cells
simultaneous resistance to many drugs
What are strategies to circumvent resistance?
increase dose
multi-drug regimens
co-admin agens that defeat resistance
recruit cells out of resting phase
What is the advantages of combination therapy?
provide maximal cell kill within range of toxicity tolerated by host of each drug
provide a braoder range of coverage
prevent development of new resistant lines
What is sequential blockade?
simultaneousl action of two inhibitors acting on different enzymes of a linera metablic pathway
What is concurrent inhibition?
inhibitors block two separate pathways that lead to the same end product
What is complementary inhibition?
one of the inhibitors affects the function of an end product the other inhbiitor affects the syntehsis of that end product
What is rescue?
rescues teh normal cells from treatment
