Cancer Pharmacology (Part 2 of 2) Flashcards
What are the important alkylating agents we talked about? (broad- 3)
nitrogen mustards, alkyl sulfonate, and platinum coordination complexes
what are two important nitrogen mustard drugs?
cyclophosphamide and ifosfamide
what is an important alkyl sulfonate drug?
busulfan
what is an important platinum coordination complex drug?
cisplatin
there are five major types of alkylating agents, what are they?
nitrogen mustards, nitrosoureas, alkyl sulfonates, methylhydrazine derivatives, and Triazines
what is an example of a nitrosoureas?
carmustine
what is an example of methylhydrazine derivatives?
procarbazine
what is an example of triazines?
dacarbazine
what is the most widely used alkylating agent and also one of the most emetogenic agents?
the nitrogen mustard- cyclophosphamide
are alkylating agents cell cycle specific or nonspecific?
cell cycle nonspecific
what is the mechanism of action of alkylating agents?
they form covalent linkages with DNA
specifically, how does cyclophosphamide work?
it targets the guanines and makes these cross links either within the same strand or across the strand- so the helicase coming down unwinding DNA can’t go any further once it hits this cross link and that leads to cell death
what does cyclophosphamide need to be activated by?
cytochrome p450
what is one of the most common atypical adverse effects of cyclophosphamide?
hemorrhagic cystitis
what causes the hemorrhagic cystitis in patients receiving cyclophosphamide?
it is due to the toxic metabolite Acrolein
what is the rescue agents that can prevent hemorrhagic cystitis caused by acrolein?
Mesna- it inactivates acrolein and is used for prophylaxis of chemotherapy induced cystitis
systemic toxicities are what?
dose related
oral administration of alkylating agents is of great clinical benefit because why?
you aren’t going to cause the injection related events such as direct vesicant effects and tissue damage at site of injection
many alkylating agents produce acute toxicity such as what? and how can you treat this?
such as nausea and vomiting; pretreat with serotonin antagonist
what are 2 atypical adverse effects of cisplatin?
renal tubular damage and ototoxicity
what is an atypical adverse effect of Busulfan?
pulmonary fibrosis
what are antimetabolites?
they are structural analogs to compounds necessary for cell proliferation; they block or subvert pathways that are involved in or lead to cell replication (nucleotide and nucleic acid synthesis)
are antimetabolites cell cycle specific or nonspecific?
cell cycle specific- they block formation of the building blocks of DNA and DNA is only built during S phase
what are the 3 main categories of antimetabolites?
folic acid analogs, pyrimidine analogs, and purine analogs
what is an example of a folic acid analog?
methotrexate
what is an example of a pyrimidine analog?
5-fluorouracil
what is an example of a purine analog?
6-mercaptopurine (6-MP)
what is the mechanism of action of methotrexate?
it inhibits dihydrofolate reductase, which means that this pathway cannot be competed to form dTMP–> dTTP–> DNA
besides the treatment of cancer, what else can methotrexate be used for?
RA and psoriasis
what is one of the atypical adverse effects of high dose methotrexate?
mucosal ulceration
what is a rescue agent for methotrexate and how does it work?
leucovorin; administration of the reduced folate leucovorin at a non-high dose–> the healthy cells will accept it but the cancer cells will not
what is the mechanism of action of flurouracil?
5-fluorouracil blocks the thymidylate synthetase–> so we can’t make dTMP–> dTTP–> DNA
what was the example fo a drug-drug interaction affecting bioavailability that we talked about?
mercaptopurine and allopurinol
what are the general characteristics of 6-MP?
it is inactive in its parent form
what metabolizes 6-MP?
HGPRT
what is the effect of xanthine oxidase on 6-MP?
it metabolizes it to the inactive metabolite 6-thiouric acid (first pass effect)
what is a drug that is a xanthine oxidase inhibitor?
allopurinol
simultaneous administration of allopurinol and PO 6-MP results in what?
increased levels of 6-MP and increased toxicity
how can you still use allopurinol and 6-MP together without toxic effects?
you need to reduce oral 6-MP dose by 50-75%; IV dose is unaffected
antimetabolites are cell cycle specific for what phase?
s-phase
what is the toxicity like of antimetabolites?
relatively little acute toxicity after an initial dose
what are common routes of administration of antimetabolites?
oral, intravenous, intrathecal (methotrexate)
what common toxicities associated with antimetabolites? (8)
diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, and hepatotoxicity
what are 6 broad classes of natural antineoplastic agents?
vinca alkaloids, taxanes, epipodophyllotoxins, antibiotics, anthracenedione, and enzymes
what are 2 examples of vinca alkaloids?
vinblastine and vincristine
what is an example of a taxane?
paclitaxel
what is an example of epipodophyllotoxins?
etoposide
what is an example of a natural antineoplastic antibiotic?
doxorubicin
what is an example of an anthracenedione?
bleomycin
what is an example of a natural antineoplastic enzyme?
l-asparaginase
where do vinca alkaloids come from?
madagascar periwinkle
what is the MOA of vinca alkaloids (vinblastine and vincristine)?
they bind to beta-tubulin and inhibit microtubule assembly –> they cause depolarization; they destabalize microtubule formation
are vinca alkaloids cell cycle specific or nonspecific?
cell cycle specific (mitosis inhibition so M-phase specific)
what are the common adverse effects of vinca alkaloids?
alopecia and bone marrow depression
what does vinblastine cause?
myelosuppression to a greater extent than vincristine
what does vincristine cause?
cumulative neurological toxicities (numbness and tingling of the extremities, loss of DTRs, motor weakness) compared to vinblastine
what is the main difference between vinca alkaloids and taxanes?
vinca alkaloids destabilize microtubule formation and taxanes stabilize microtubule formation
what is the MOA of taxanes?
they bind to beta-tubulin and stabilize microtubule formation
is taxane cell cycle specific or nonspecific?
cell cycle specific- mitosis inhibition- so specific to M phase
what are two examples of taxanes?
paclitaxela dn docetaxel
what are the adverse effects of paclitaxel?
hypersensitivity reactions in hands and toes, change in taste
what are the characteristics of docetaxel?
greater cellular uptake and retained intracellularly longer than paclitaxel, leading to smaller dose and less side effects
what are the side effects of docetaxel?
hypersensitivity, neutropenia, and hair loss
what was the traditional use of taxanes used for?
breast cancer
inhibition of topoisomerase enzymes causes what?
DNA damage and leads to cell death
which drugs inhibit topoisomerase I?
camptothecins (topotecan and irinotecan)
which drugs inhibit topoisomerase II?
epipodophyllotoxins and anthracycline antibiotics
what are 2 examples of epipodophyllotoxins?
etoposide and teniposide
what are 2 examples of anthracycline antibiotics?
doxorubicin and daunorubicin
are topoisomerase inhibitors cell cycle specific or nonspecific?
cell cycle specific (primarily S; also G1 and G2)
all of the anticancer antibiotics currently in use are products of what?
various strains of the soil microbe Streptomyces
what are the effects of antitumor antibiotics?
mainly on DNA
what are 4 broad examples of effective antitumor antibiotic agents?
anthracyclines, dactinomycin, bleomycin, and mitomycin
what is the MOA of anthracyclines?
Topoisomerase II inhibitor and DNA intercalation
are anthracyclines cell cycle specific or nonspecific?
cell cycle non specific
what is super important to remember about anthracyclines (what do they produce)?
they produce free radicals, and these free radicals can lead to significant cardiotoxicity
cumulative cardiac damage can lead to what?
dysrhythmias and heart failure
what is the MOA of bleomycin?
single and double stranded DNA breaks
what is the atypical adverse effect associated with bleomycin?
causes significant pulmonary toxicity and usually presents as pneumonitis with cough, dyspnea, and dry inspiratory crackles
what is the MOA of dactinomycin?
intercalation of DNA
what is a specific example of anthracyclines?
doxorubicin
what are the natural antineogenic agents: enzymes: asparaginase and pegaspargase used for?
targeted therapy for acute lymphoblastic leukemia (ALL)
ALL tumor cells lack what?
the enzyme asparagine synthetase, and because they lack that enzyme they require an exogenous source of L-asparagine
what is the MOA of asparaginase and pegaspargase?
they hydrolyze circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
are natural antineogenic enzymes: asparaginase and pegaspargase cell cycle specific or non specific?
cell cycle specific (G1)
what are the adverse side effects associated with asparaginase and pegaspargase?
acute hypersensitivity: fever, chills, nausea, vomiting, skin rash, and urticaria
what are the delayed toxicities associated with asparaginase and pegaspargase?
increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma
the t(15;17) translocation creates what fusion protein?
PML-RARalpha
what does the fusion protein PML-RARalpha inhibit?
granulocytic maturation in APL
what is an example of a differentiating agent and what is it used for?
tretinoin (all-trans-retinoic acid) binds to the PML-RAR alpha fusion protein and anatagonizes (aka blocks) the inhibitory effect on the transcription of target genes
what happens after administration of tretinoin (all-trans-retinoic acid)?
within 1-2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die
what are common adverse effects associated with use of tretinoin (all-trans-retinoic acid)?
vitamin A toxicity and retinoic acid syndrome
what happens when tyrosine kinases are mutated, overexpressed, or structurally altered?
they can become potent oncoproteins
what antineoplastic agents target intracellular tyrosine kinases?
-nibs
what antineoplastic agents target extracellular tyrosine kinases?
-mabs
what is the result from the t(9:22) translocation?
the BCR-ABL fusion protein–> CML
what can treat CML?
imatinib
besides inhibiting the ABL tyrosine kinase, what else can imatinib inhibit?
the RTKs PDGFR and KIT
what is erlotinib and gefitinib?
tyrosine kinase domain inhibitors of the EGFR
what is erlotinib and gefitnib used for?
refractory non-small cell lung cancer, pancreatic cancer
what toxicities do erlotinib and gefitnib produce?
dermatologic toxicities
if patients are diagnosed with a cancer that has a high activity of VEGFR, what can they be treated with?
ziv-aflibercept
what is ziv-aflibercept?
recombinant fusion protein made up of portions of the extracellular domains oh human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1 molecule–> inhibits VEGFR signaling
what is the MOA of growth factor receptor inhibitors?
inhibit growth factor receptor signaling
what is the MOA of tyrosine kinase inhibitors?
inhibit tyrosine kinase activity
what is the mechanism of resistance for tyrosine kinase and growth factor receptor inhibitors?
point mutations in drug binding sites
what are common adverse effects seen with tyrosine kinase and growth factor receptor inhibitors?
nausea and vomiting; acneform skin rash and hypersensitivity (allergic reaction)
what are biological response modifiers?
agents that act indirectly on the immune system to mediate their antitumor effects by enhancing the immunologic response to neoplastic cells
what are two examples of biological response modifiers?
interferons (interferon-alpha2a and alpha 2b) and interleukin-2
what is the effect of interferons?
they inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages
what adverse effects can interferons cause?
bone marrow depression, neutropenia, anemia, renal toxicity, edema, and arrhythmias
what is the effect of interleukin-2?
it increases the cytotoxic killing by T cells and NK cells
what is the major toxicity associated with interleukin-2?
capillary leak syndrome
what is the MOA of antibodies used to treat neoplastic disorders?
the antigen
rituximab targets what antigen? and what is this used to treat?
CD20; non-hodgkin’s lymphoma
what are the most active cytotoxic agents used to treat malignant melanoma?
dacarbazine and cisplatin; but the response rate to these agents is low
what biological agents are used to treat malignant melanoma?
IFN-alpha and interleukin-2
what are the target therapies that have been used to treat malignant melanoma based on the genotypic analysis?
nivolumab and pembrolizumab
what does nivolumab and pembrolizumab target?
the BRAF V600E mutation that is present in a large majority of melanomas
what three drugs target BRAF directly?
vemurafenib, dabrafenib, and encorafenib
