Cancer Treatment Flashcards
Antimetabolites
cytarabine, 5-fluorouracil, mercaptopurine, methotrexate, thioguanine
Antitumor Antibiotics
bleomycin, dactinomycin, doxorubicin
Alkylating Agents
carmustine, dacarbazine, lomustine, mechlorethamine
Mitotic Inhibitors
docetaxel, paclitaxel, vinblastine, vincristine
Steroid Hormones and Antagonists
aminoglutethimide, anastrozole, bicalutamide, exemestane, flutamide, goserelin, letrozole, leuprolide, nilutamide, prednisone, tamoxifen
Monoclonal antibodies
bevacizumab, retuximab, trastuzumab
Other Anticancer drugs
carboplatin, cisplatin, interferons, oxaliplatin
T/F 25 percent of the US population will face a diagnosis of cancer
true
What are three types of treatment for cancer?
surgery, local radiation, systemic chemotherapy
What is the overall 5 year survival rate for cancer patients?
65%
What is the goal of chemotherapy?
cause a lethal cytotoxic event or apoptosis in the caner cell, arresting the tumor progression
Where is the chemotherapy attack directed?
DNA or metabolic sites essential to cell replication
T/F there are steep dose-response curves for both toxic and therapeutic effects
true, chemo effects all kinds of proliferating cells not just malignant cells
What is the ultimate goal of treatment?
a cure, long term disease free survival, requires eradication of every neoplastic cell
What is the goal of cancer treatment if a cure is not attainable?
control of the disease, stop the cancer from enlarging and spreading and allow patient to maintain a normal existence
How is the neoplastic cell burden usually initially reduced?
surgery and or radiation, followed by chemotherapy, immunotherapy etc
What are indications for chemotherapy?
when tumor cells are not amenable to surgery, as supplemental treatment after surgery or radiation, to shrink tumor prior to surgery, or to prolong remission
How does the cell growth cycle relate to tumor susceptibility?
rapidly dividing cells are usually more susceptible, while non-proliferating cells (G0) usually survive toxic effects of therapy
How does the tumor growth rate work?
growth rate of tumors is initially rapid but slows as tumor size increases because nutrients and oxygen decrease
What cell cycle “stage” does surgery or radiation shift remaining cell types to?
active proliferation, making them more susceptible to chemotherapy
What is log kill?
destruction of cancer cells follows first-order kinetics so a given dose destroys constant fraction of cells
What is a pharmacologic sanctuary?
some tumor cells can hide in tissues where chemotherapeutic agents can not enter, like the CNS
What two treatments are aimed at “finding” the tumor?
radiation and alternative administration of drugs
What is a typical cancer treatment protocol?
combination of drugs is more successful, use agents with different toxicities and different MOAs
T/F if two drugs are combined for cancer therapy that have similar toxicities, you must decrease the dose of both
true
What are the advantages of combination drug treatment?
provide maximal killing with tolerated toxicity, effective against broad cell lines, may delay development of resistant cell lines
T/F some cells are inherently resistant to anticancer drugs
true
What are two mechanisms by which multidrug resistance occurs?
transmembrane protein (p-glycoprotein) can pump anticancer drugs out of tumor cells, high concentration of some drugs can inhibit the pump
Which cells are particularly susceptible to toxicity?
those that undergo rapid proliferation: lining of cheeks, bone marrow, GI mucosa, hair follicles
T/F chemotherapeutic agents have a broad therapeutic index
false, narrow
What are the most common adverse effects to cancer treatment?
severe vomiting, bone marrow suppression, alopecia and myelosuppression
What are treatment induced tumors?
chemotherapeutic agents are mutagens, neoplasms can arise 10 or more years after the original cancer was cured, especially with alkylating agents
What is the MOA of antimetabolites?
interefere with the availability of normal nucleotide base precursors by either inhibiting synthesis or competing with them in DNA or RNA synthesis
Are antimetabolites cell cycle specific or not?
cell cycle specific, maximal effects in S phase
What is dihydrofolate reductase?
the enzyme that converts folic acid to active form (tetrahydrofolic acid) which is essential for cell replication
What is the MOA of methotrexate?
dihydrofolate reductase antagonist, leads to decreased production of required nucleic compounds aka DNA, RNA, and protein synthesis is depressed leading to cell death
How can you reverse methotrexate?
use a thousandfold excess dihydrofolate or administer leucovorin
What is leucovorin?
it has a similar structure to folic acid and bypasses blocked enzyme and replenishes folate pool
Which cells are resistant to methotrexate?
non-proliferating cells
What drug in low doses can treat some inflammatory diseases as an antimetabolite?
methotrexate
What three inflammatory diseases can methotrexate treat?
severe psoriasis, rheumatoid arthritis, Crohn’s disease
How is methotrexate administered?
oral, IM and IV (intrathecal)
Does methotrexate penetrate the CNS?
no, requires intrathecal
Why must a patient on methotrexate be hydrated?
to prevent renal toxicity which can lead to crystalluria
What are the adverse effects of methotrexate?
GI upset, toxicities in constantly renewing tissues (rash, urticaria, alopecia, stomatitis, erythemia), renal damage, cirrhosis
What is the adverse effect of methotrexate in children?
pulmonary toxicity
What are the contraindications of methotrexate?
pregnancy
What is the MOA of mercaptopurine?
nucleotide formation, inhibition of protein synthesis, and incorporation into nucleic acids for RNA and DNA
What are pharmacokinetic considerations for mercaptopurine?
incomplete absorption orally, reduced bioavailability by first pass… still given orally though
What are the adverse effects of mercaptopurine?
bone marrow depression, anorexia + GI upset, jaundice
What is the MOA of thioguanine?
same as 6-MP, nucleotide formation, inhibition of protein synthesis and incorporation into nucleic acids for RNA and DNA
What are the pharmacokinetic considerations of thioguanine?
incomplete oral absorption w/ first pass, some people accumulate higher concentrations of metabolites leading to high myelosuppression and secondary malignancies (genotyping recommended)
What are the adverse effects of thioguanine?
dose-related bone marrow depression and risk of liver toxicity with long-term use
Is thioguanine used as a maintenance therapy?
no
What is the MOA of 5-fluorouracil?
enters cell through carrier-mediated transport system, forms a molecular complex that deprives the cell of thymidine stoping DNA synthesis
What is given in combination with 5-FU (fluorouracil)?
leucovorin which helps 5FU work longer
How is 5FU administered?
IV or topically
What are some reasons 5FU is given topically?
skin cancer, prevention of scar tissue formation in surgery, in some ocular surgeries
Does 5FU penetrate the CNS?
yes
How is 5FU excreted?
kidney and lungs
What are the adverse effects of 5FU?
GI upset, ulceration of oral and GI mucosa, bone marrow depression, anorexia
What is the MOA of cytarabine?
enters cell via carrier-mediated process and inhibits DNA polymerase and also can be incorporated into cellular DNA
Which cell cycle phase does cytarabine act during?
S phase specific
How is cytarabine administered?
IV only, new preparation allows penetration to CSF
How is cytarabine excreted?
kidney
What are the adverse effects of cytarabine?
GI upset, sever myelosuppression, hepatic dysfunction, CHEMICAL CONJUNCTIVITIS at high doses
What is the MOA of antitumor antibiotics?
cytotoxic due to interactions with DNA that prevent RNA synthesis and leads to the formation of toxic free radicals
Are anti-tumor antibiotics cell-cycle specific?
mostly no
What is the first antibiotic to find use in tumor chemotherapy?
dactinomycin
What is dactinomycin sometimes combined with?
methotrexate
What is the MOA of dactinomycin?
inserts into double helix and interferes with RNA polymerase
How is dactinomycin administered?
IV
Does dactinomycin penetrate the CSF?
no
How is dactinomycin excreted?
via bile
What are the adverse effects of dactinomycin?
bone marrow suppression, immunosuppression, GI upset, alopecia, stomatitis, sensitization to radiation
What is doxorubicin?
one of the most widely used anticancer drugs– the red devil
What are the analogues of doxorubicin?
idarubicin and epirubicin
What is the MOA of doxorubicin?
induce cytotoxicity and produce free radicals that damage the cells’ DNA
How is doxorubicin administered?
IV, deactivated in the GI tract
What does extravasation of doxorubicin lead to?
tissue necrosis
How is doxorubicin metabolized and excreted?
extensive liver metabolism and bile excretion
Why is doxorubicin the red devil?
veins may appear dark red surrounding site of infusion and urine will be red
What are the adverse effects of doxorubicin?
CARDIOTOXICITY (irreversible), bone marrow suppression, stomatitis, GI upset, severe alopecia
What is the MOA of bleomycin?
oxidative scission of DNA
Is bleomycin cell cycle specific?
yes, causes cells to accumulate in G2
What is bleomycin used to treat?
testicular cancers
How is bleomycin administered?
subc, IM, IC
What is true of bleomycin absorption?
inactivating enzyme is present in liver and spleen, low in lungs, absent in skin
How is bleomycin excreted?
kidney
What are the adverse effects of bleomycin?
PULMONARY TOXICITY, alopecia, fever and chills, hypertrophic skin changes and HYPERPIGMENTATION
What is the MOA of alkylating agents?
cause alkylation of DNA by addition of carbon chain to beginning of molecules which alters structure and function
Are alkylating agents cell cycle specific?
no, used mainly for slow growing tumors
T/F all alkylating agents are mutagenic and carcinogenic
true, can lead to secondary malignancies, especially leukemia
What drug was developed as mustard gas during WWI?
meclorethamine
What is the MOA of meclorethamine?
transported into cell, cross links with DNA guanine bases, cause strand breakage and occasional miscoding mutations
What are the pharmacokinetic considerations of meclorethamine?
very unstable, blistering agent, only given IV, and has almost no drug excretion
What are the adverse effects of meclorethamine?
severe GI, severe bone marrow depression, latent viral infections due to immunosuppression
What is the MOA of carmustine and lomustine?
alkylation of DNA that inhibits replication and eventually RNA and protein synthesis
What are carmustine and lomustine primarily used for?
treatment of brain tumors since they penetrate CNS
What are closely related nitrosoureas specifically toxic to beta cells of the pancreas?
carmustine and lomustine
When are carmustine and lomustine cytotoxic?
in actively dividing cells, alkylate DNA in all cell cycle phases
How are carmustine and lomustine administered?
IV and oral respectively
How are C and L excreted?
kidney
What are adverse effects of C and L?
delayed hematopoietic depression (decreased formation of blood cells), development of aplastic marrow, renal toxicity and pulmonary fibrosis
What is dacarbaxine used to treat?
melanoma
What is the MOA of dacarbazine?
attacks nucleophilic groups in DNA and must undergo biotransformation to an active metabolite
How is dacarbazine administered?
IV
What are the adverse effects of dacarbazine?
GI, myelosuppression, hepatotoxicity
What are mitotic spindles?
chromatin and microtubules needed for movement of DNA in cell division
What is the MOA of vincristine and vinblastine?
bind to microtubular protein and prevent polumerization aka no formation of spindle
Are vincrisitne and vinblastine cell cycle specific?
yes
How are V and V administered?
IV
T/F V and V are metabolized by the P450 system
true
How are V and V excreted?
bile and feces
What are adverse effects of V and V?
hyperuricemia (gout), GI, alopecia, phlebitis or cellulitis if extravasation occurs
What is the MOA of paclitaxel and docetaxel?
bind to tubulin subunit and promote stabilization of microtubules (overly stable microtubules are nonfunctional)
What are the pharmacokinetics of paclitaxel and docetaxel?
IV infusion, P450 metabolism and biliary excretion
What are the adverse effects of paclitaxel and docetaxel?
neutropenia, peripheral neuropathy, hypersensitivity reaction
Which typical adverse effect is uncommon with paclitaxel and docetaxel?
vomiting and diarrhea, instead there is fluid retention
What is the contraindication of paclitaxel and docetaxel?
cardiac disease
Steroid hormone sensitive tumors may be ___ or ____
hormone responsive or dependent (or both)
What is hormone responsive?
tumor regresses following treatment with specific hormone
What is hormone dependent?
removal of hormone results in tumor regression
What is prednisone used for?
treatment of lymphomas, used to induce remission
What is the MOA of prednisone?
triggers production of specific proteins that reduce cell growth and proliferation
What are the pharmacokinetics of prednisone?
readily absorbed orally, liver metabolism, excreted in urine
What are the adverse effects of prednisone?
predisposed patient to infection, hyperglycemia, cataract formation, increased IOP, osteoporosis, mood changes
What adverse effects are the same for all corticosteroids and anti-inflammatory cancer tx?
predispose to infection, hyperglycemia, cataract formation, increased IOP, osteoporosis, mood changes
What is tamoxifen?
an estrogen antagonists used for breast cancer
T/F tamoxifen can be used prophylactically in women at high risk
true, but must be discontinued after 5 years or drug resistant tumors can develop
What is the MOA of tamoxifen?
binds estrogen receptor as antagonist preventing RNA synthesis, results in depletion of estrogen receptors
What is tamoxifen given with in premenopausal women?
an agent that lowers estrogen levels since the drug competes with estrogen
Is tamoxifen cell cycle specific?
no
How is tamoxifen administered?
orally
How is tamoxifen metabolized and excreted?
partially metabolized in liver and excreted through bile
T/F some metabolites of tamoxifen have agonist activity?
true
What are adverse effects of tamoxifen?
hot flashes, GI, skin rash, potential for endometrial cancer because of decreased estrogen
What is the retinal adverse effect of tamoxifen?
crystalline retinopathy and other vision problems, may see deposits in the cornea
What is an aromatase reaction responsible for?
extra adrenal synthesis of estrogen, important source of estrogen in postmenopausal women
What do aromatase inhibitors do?
decrease production of estrogen, treatment of breast cancer
What was the first developed aromatase inhibitor?
aminoglutethimide
What is aminoglutethimide normally taken with?
hydrocortisone
What are anastrozole and letrozole?
nonsteroidal but more selective and potent aromatase inhibitors– does not need hydrocortisone supplementation and does not predispose to endometrial cancer
What is exemestane?
steroidal inhibitor of aromatase
What are the pharmacokinetics of aromatase inhibitors?
well absorbed orally, p450 metabolism, urine excretion
What are leuprolide and goserelin?
analogs of gonadotrophin releasing hormone, act as agonists
What is the MOA of leuprolide and goserelin?
binding to receptor causes desensitization and a decrease in FSH and LH so androgen and estrogen synthesis is reduced
What are leuprolide and goserelin used for?
prostate cancer and advanced breast cancer
What are two names for estrogens?
ethinyl estradiol and diethylstilbestrol
What is estrogen used for?
treatment of prostate cancer
What is the MOA of estrogen use?
blocks production of LH and decrease synthesis of androgens in the testis
What are the adverse effects of estrogens?
thromboemboli, MI, stroke, hypercalcemia, gynecomastia and impotence
What are flutamide, nilutamide, and bicalutamide?
nonsteroidal antiandrogens
What are nonsteroidal antiandrogens (ex: flutamide) used for?
treatment of prostate cancer
What is the MOA of nonsteroidal antiandrogens?
compete with natural hormone for androgen receptor, prevent translocation of hormone into nucleus
What is the pharmacokinetics of nonsteroidal antiandrogens?
flutamide, nilutamide and bicalutamide, oral administration, kidney excretion
What is an adverse effect of nilutamide?
visual problems
What are monoclonal antibodies?
antibodies produced by one type of immune cell and all identical clones
What is an advantage of monoclonal antibodies?
can create an antibody that can bind to any substance
What is a good target for a monoclonal antibody?
cancer cell antigens
How is the monoclonal Ab hybrid cell formed?
mice b lymphocytes fused with a tumor cell and then cloned to produce antibodies for a single antigen type
How are monoclonal antibodies administered?
injection, cannot be oral because protein structure will break down
What is the MOA of monoclonal antibodies?
bind to cancer specific antigens and induce an immunological response like apoptosis, growth inhibition, or interferes with cellular function OR cell is modified to deliver toxin or other active molecule
What was the mAb approved to treat cancer?
rituximab
What does rituximab treat?
lymphomas and leukemias
What is the MOA of rituximab?
binds to site on B lymphocyte and recruits immune effector functions to induce cell mediated cytotoxicity
What is the administration of rituximab?
IV infusion
What does trastuzumab treat?
attaches to breast cancer-specific receptor and cells undergo G1 arrest and reduction of proliferation (reduces rate of relapse by 50% during first year.
What is bevacizumab?
antiangiogenesis agent
What is the MOA of bevacizumab?
attaches to a stops vascular endothelial growth factor from stimulating the formation of new blood vessels which decreases oxygen supply to tumor cells
What is bevacizumab used to treat?
retinal neovascular diseases like diabetic ret, choroidal neo-vascularization etc (avastin)
What is the MOA of platinum coordination complexes?
similar to alkylating agents, bind guanine and cross link DNA
What are the pharmacokinetic considerations of platinum coordination complexes?
IV administration, little CSF penetration, renal excretion
What are the adverse effects of cisplatin?
sever vomiting, nephrotoxicity, and ototoxicity
What are the adverse effects of carboplatin and oxaliplatin?
mild nausea and myelosuppression
What is interferon alpha?
primarily leukocytic
What is interferon beta?
produced by connective tissue fibroblasts
What is interferon gamma?
produced by t lymphocytes
What interferons are used to treat neoplastic disease?
alpha 2a and 2b
What is the MOA of interferons?
binding of interferon produces complex intracellular reactions that increase inflammation and decrease growth (enzyme synthesis, suppression of cell proliferation, activation of macrophages, increased cytotoxicity of lymphocytes)
What are the pharmacokinetics of interferons?
IM or subc injection (or IV form of 2b), minimal liver metabolism, and excretion by kidneys
