082914 antineoplastics part two Flashcards
alkylating agents mechanism
introduce alkyl groups into DNA, RNA, proteins (DNA is likely the most important target)
causes DNA crosslinks, strand breaks, misreading of code
cell cycle specificity of alkylating agents
can be:
cell cycle non specific (also affect G0 cells)–ex are mechlorethamine, carmustine
cell cycle specific phase nonspecific-ex are cyclophosphamide
what is unique of the alkylating agents?
least selective of the antineoplastics (tend to kill tumor and normal cells equally)
toxicities of alkylating agents
mechlorethamine-nausea and vomiting, myelosuppresion
carmustine-nausea and vomiting, delayed myelosuppression
cyclophosphamide-nausea and vomiting, limited myelosuppression, alopecia
what are the typical side effects of alkylating agents in general? (not for specific drugs)
hematopoeisis suppression (often used as indicator of therapeutic effectiveness and normal cell recovery)
GI effects (damage to intestinal mucosa…nausea and vomiting
alopecia
affect RAPIDLY DIVIDING tissues most
what two drugs are examples of nitrogen mustards in alkylating agents?
mechlorethamine
cyclophosphamide
what drug is an ex of nitrosoureas in alkylating agents?
carmustine
mechlorethamine cell cycle specificity
cell cycle nonspecific
what is mechlorethamine used for
in combo therapy for Hodgkin’s and non-Hodgkin’s LYMPHOMA
breast, lung, ovarian cancer
MOA of mechlorethamine
bifunctional alkylating agent: produces DNA cross links highly reactive (disappears from blood in seconds to minutes)
what is the cell cycle specificity of cyclophosphamide
cycle specific phase nonspecific
what is unique about cyclophosphamide?
PRODRUG activated by liver cytochrome P450s
actual alkylating agent is phosphoramide mustard
toxicity of cyclophosphamide
bladder toxicity-sterile hemorrhagic cystitis (can be partially prevented with mesna)
what is good about cyclophosphamide?
very broad spectrum of activity, so used against wide variety of cancers
BREAST CANCER
cell cycle specificity of carmustine
cycle nonspecific
what is unique about carmustine?
crosses BBB very well
uses of carmustine
brain tumors, multiple myeloma, melanoma
when are antimetabolites most effective?
against tumors where cell proliferation is rapid
cell cycle specificity of antimetabolites
S phase specific
what are antimetabolites?
structural analogs of precursors of nucleic acid synthesis or other related pathways
MOA of methotrexate and what type of drug is it?
type: antimetabolite
MOA: binds to dihydrofolate reductase and prevents formation of tetrahydrofolate, which is needed for synthesis of dTMP
leucovorin rescue
high doeses of methotrexate are necessary to bind all dihydrofolate reductase
rescue host cells with leucovorin–leucovorin is folinic acid, which is a fully reduced folate that does not require to be reduced by DHFR (normal cells have increased ability to bring in leucovorin relative to tumor cells)
side effects of methotrexate
intestinal epithelium damage
bone marrow suppression
renal tubular necrosis
displaces other drugs from serum albumin
uses of methotrexate
acute lymphocytic leukemia
choriocarcinoma (methotrexate is #1 drug for this)
head neck breast lung
osteosarcoma
fluorouracil: type of drug and MOA
antimetabolite
pyrimidine analog that is activated in cells to FUTP which inhibits RNA synthesis. also activated to FdUMP which interferes with thymidylate synthase and ultimately DNA synthesis
side effects of fluorouracil
nausea, anorexia, diarrhea
myelosuppression
uses of fluorouracil
BROAD spectrum:
COLON, BREAST, stomach, pancreas, ovary, head, neck, bladder (mostly GI)
basal cell carcinoma
cytarabine: type of drug and MOA
antimetabolite
pyrimidine (cytidine) analog that competes for phosphoyrlation of cytidine; competes for incorrporation into DNA and causes chain termination
side effects of cytarabine
marked myelosuppresion (limits dose) neurotoxic
uses of cytarabine
acute leukemias (acute myelocytic leukemia for ex)
mercaptopurine: type of drug and MOA
antimetabolite
purine analog-converted in cells to ribonucleotide that inhibits RNA and DNA synthesis
sides effects of mercaptopurine
bone marrow depression
vomiting, nausea, anorexia
jaundice
uses of mercaptopurine
acute leukemias
TPMT is important for mercaptopurine b/c?
TPMT degrades mercaptopurine (6MP) to inactive form of 6 methyl MP. If person has non functional allele for it, has increased risk of serious bone marrow toxicity with normal dose
if pt has two copies of nonfunctional TPMT, then can’t tolerate the 6MP
hydroxyurea: type of drug and MOA
antimetabolite
inhibits ribonucleotide reductase (blocks conversion of ribonucleotides to dNTPs, preventing DNA synthesis
arrests cells then at G1-S point
major uses of hydroxyurea
granulocytic leukemia
side effects of hydroxyurea
hematopoietic depression
GI disturbances
examples of the vinca alkaloids, and what class of drug are the vinca alkaloids?
vincristine, vinblastine
class: natural products
MOA of vinca alkaloids
binds to tubulin, inhibiting proper formation of microtubules and mitotic spindle
arrests cells in metaphase
how are vincristine and vinblastine similar or different?
similar in that structurally related
different in their toxicities and their antitumor spectrum
side effects of vinblastine
strongly myelosuppressive
epithelial ulcerations
side effects of vincristine
significantly less bone marrow toxic. than vinblastine
alopecia, neuromuscular abnormalities (peripheral neuropathy)
uses of vinblastine
lymphomas, breast cancer
uses of vincristine
acute lymphocytic leukemia
lymphomas
Wilm’s tumor
neuroblastoma
MOA of taxanes and what class are taxanes under?
class: natural products
MOA: enhances assembly and stability of microtubules by binding to beta subunit of tubulin, blocks late in G2 phase (this phase is more sensitive to radiation so paclitaxel may be used as a radiosensitizer)
paclitaxel is an example of what type of drug? what class?
taxane, natural products
uses of paclitaxel
refractory ovarian cancer
breast cancer
sides effects of paclitaxel
dose limiting leukopenia
peripheral neuropathy
myalgia, arthralgia
doxorubicin: drug type/class?
antitumor antibiotic, natural products
cell cycle specificity of doxorubicin
cycle specific phase non specific
uses of doxorubicin
wide spectrum of activity
lymphomas, breast, ovary
most widely prescribed agent in its class
MOA of doxorubicin
intercalates in DNA, distorting the DNA helix
binds to DNA and topoisomerase II
causes lipid peroxidation and free radical generation
which drug has as a side effect CARDIOMYOPATHY?
doxorubicin
side effects of doxorubicin
cardiomyopathy
bone marrow depression
alopecia
GI problems
bleomycin: class of drug
natural products
MOA of bleomycin
mix of IRON-containing glycoypeptides that bind to DNA
causes oxidative-like damage to DNA which lead to DNA strand breaks
cell phase specificity of bleomycin
phase specific for G2
uses of bleomycin
germ cell tumors of testes and ovaries
head, neck, lung, lymphomas
side effects of bleomycin
minimal myelosuppression
PULMONARY TOXICITY
skin vesiculation, hyperpigmentation
*lung and skin have lowest levels of bleomycin hydrolase for inactivating the drug
etoposide: class of drug
natural compounds
MOA of etoposide
irreversibly stabilizes DNA-topoisomerase II complexes (causing dsDNA breaks that can’t be repaired)
cell cycle specificity of etoposide
late G2 phase
uses of etoposide
lymphomas, acute leukemia, small cell lung, testis
side effects of etoposide
leukopenia nausea vomiting diarrhea alopecia
biological response modifiers
naturally occurring proteins designed to mimic natural proteins
limitation is that response can be variable,;serious side effects have happened
filgrastim
goal is to limit chemo-induced neutropenia
promotes progenitors of neutrophils
side effect of filgrastim
bone pain
trastuzumab drug type and class
monoclonal antibodies, natural compounds
MOA of trastuzumab
humanized monoclonal antibody that binds to HER2 (human epidermal growth factor) receptor to block proliferation of cells; may illicit immune response against HER2+ cells
uses of trastuzumab
breast cancers that overexpress HER2, so is a target therapy
side effects of trastuzumab
cardiomyopathy-often reversible
hypersensitivity
infusion rxns-fever, chills
cisplatin: class of drug?
miscellaneous agents
MOA of cisplatin
platinum coordination complex-hydrolysis yields activated species which causes DNA crosslinks
cell cycle specificity of cisplatin
cycle specific phase non specific
uses of cisplatin
wide spectrum
testicular cancer
ovarian cancer
side effects of cisplatin
NEPHROTOXICITY ototoxicity peripheral neuropathy electroylyte distrubances nausea, vomiting mylosuppression
MOA of procarbazine
activated in vivo to a methylating agent which causes chromosomal damage
an atypical alkylating agent
uses of procarbazine
Hodgkin’s lymphoma
side effects of procarbazine
myelosuppression, nausea, vomiting
uses of hormone and hormone antagonist therapies against cancer
good for tumors that are steroid hormone dependent
possible strategies for hormone therapy against cancer
opposite steroidal compounds (estrogens for prostate cancer, etc)
anti-hormonal compounds
benefits of hormonal therapy against cancer
responses to it can be dramatic and prolonged
and has other beneficial side effects (not just for tumor)-ex is progestins as an appetite stimulant for cancer pts
prednisone MOA
binds to steroid receptors which act to modulate several aspects of cell growth (may arrest cells at G1; depress expression of many growth-related genes, induce nucleases which may modulate cell lysis)
what forms of antiestrogenic therapies are used to treat cancer?
estrogen receptor antagonists (tamoxifen, raloxifene)
aromatase inhibitors (letrozole)
advantages of nonsteroidal aromatase inhibitors
oral, rapid onset
estrogen below detectable levels
no androgenic side effects
tamoxifen MOA
antiestrogen that compoetitively blocks estrogen receptors in breast tissue (estrogen agonist bone tissue)
cell cycle specificity of tamoxifen
cytostatic
tumor regrows when tamoxifen is removed
uses of tamoxifen
advanced post menopausal breast cancer
premenopausal metastatic breast cancer
breast cancer prophylaxis
what is tamoxifen activated by?
CYP2D6
side effects of tamoxifen and letrozole
nausea
menopause like symptoms
fatigue
bone and other musculoskeletal pain
MOA of letrozole
blocks conversion of androgens to estrogens by inhibiting aromatase
uses of letrozole
1st line treatment of post menopausal locally advanced or metastatic breast cancer
what are some antiandrogenic approaches to prostate cancer?
GnRH analogs (leuprolide) non-steroidal androgen receptor blockers (flutamide)
leuprolide MOA
analog of GnRH (initially stimulates LH and FSH release causing testosterone surge, but after 2-4 weeks, it desensitizes GnRH signaling, decreasing LH/FSH and decreasing testosterone
uses of leprolide
advance hormonally response prostate cancer
side effects of leprolide
hot flashes
impotence
flutamide MOA
nonsteroidal antiandrogen that blocks androgen receptor
uses of flutamide
treatment of metastatic prostate cancer
side effects of flutamide
gynecomastia
diarrhea
hepatotoxicity
cell cycle specificies of all the antineoplastics
see part one lecture with three slides
major cause of chemotherapeutic failure
selection and overgrowth within tumor-resistance
what is a key strategy in overcoming resistance from tumor cells with chemotherapy?
combination therapy
how does multi-drug resistance occur?
mediated by ATP-dependent drug efflux pumps
principles of combination chemotherapy
different cell cycle specificites (to hit both those in and out of cell cycle)
active as single agents
non-overlapping toxicities
different MOA
sequential blockade
simultaneous action of two inhibitors acting on different steps of linear metabolic pathway
concurrent inhibition
inhibitors block two sepearte pathways that lead to same end product
complementary inhibition
one drug affects fxn of an end product and the other drug affects the synthesis of that end product
ex: cytarabine and doxorubicin
rescue
rescue the pt’s normal cells from the cancer treatment
examples:
leucovorin (folinic acid) to rescue cells after high dose methotrexate
autologous bone marrow or stem cel transplant
synchronization
synchronize cells so they are in one phase and then use drug specific for that phase
ex: low doses of fluorouracil to block in S phase, then high dose of cytarabine to kill in S phase
recruitment
mobilize slowly proliferatin or non proliferating cells to more rapid proliferation-bring cells out of G0 and back into cell cycle and then hit them with cycle specific drugs
