ICL 12.1: Overview of Systemic Chemotherapies Flashcards
1
Q
what is precision medicine?
A
take a tumor and figure out what’s molecularly wrong with the tumor
then you design the drug to interfere with the molecular defects
2
Q
what is personalized medicine?
A
you take an individuals cancer and design drugs that will work for that person
3
Q
what is systemic therapy?
A
any therapy that is delivered to the total body compartment by the blood stream
they don’t effect the CNS because systemic therapies can’t cross the blood-brain barrier…
4
Q
what type of treatments are classified as systemic therapies?
A
chemotherapies
molecular targeted agents
antibodies
hormone-targeted agents
immunotherapies
vaccines
5
Q
which drugs are antimetabolites?
A
- antifolates/folic acid analogs
- fluoropyrimidines
- cytarabine
- gemcitabine
- azacytidine
- decitabine
- thiopurines
- purine analogs
6
Q
which drugs are antifolates?
A
antifolates are a type of antimetabolite
aka folic acid analogs
- methotrexate
- pemetrexed
- pralatrexate
7
Q
which drugs are fluoropyrimidines?
A
fluoropyrimidines are a type of antimetabolite
- 5-FU
- capecitabine
- TAS-102
8
Q
which drugs are thiopurines?
A
thiopurines are a type of antimetabolite
- 6-mercaptopurine
- 6-thioguanine
9
Q
which drugs are purine analogs?
A
purine analogs are a type of antimetabolite
- fludarabine*
- cladribine
- clofarabine
- nelarabine
10
Q
what are gemcitabine, azacytidine, decitabine?
A
nucleoside analogs
base + sugar
11
Q
what’s are two important property of anti-metabolites?
A
must be metabolized to their active form
they act in the S phase of the cell cycle!!
12
Q
what are anti-metabolites?
A
designed to block DNA synthesis
antimetabolites are supposed to act better on rapidly dividing cells which is based on the idea that cancer cells divide more rapidly and go through S phase more often than normal cells so more vulnerable
originally considered to be cytostatic rather than cytotoxic but now it’s recognized that many produce cell death by triggering apoptosis
most are nucleoside analogues that interfere with DNA synthesis or block methylation of uracil to thymidylate
13
Q
which types of cells are more vulnerable to antimetabolites?
A
GI and skin
because they have high turnover
14
Q
what do antimetabolites do?
A
compete, replace or inhibit a specific metabolite of a cell and thereby interferes with the cell’s normal metabolic functioning
15
Q
what are the three sub-classes of antimetabolites?
A
- folic acid analogs = inhibit folate dependent reactions in the cell
- pyrimidine analogs
- purine analogs and related inhibitors
16
Q
which drugs are folic acid analogs?
A
- methotrexate
- pemetrexed
- pralatrexate
17
Q
which drugs are pyrimidine analogs?
A
- fluorouracil
- cytarabine
- gemcitabine
18
Q
which drugs are purine analogs?
A
- mercaptopurine
2. pentostatin
19
Q
which disease is pentostatin used to treat?
A
hairy cell leukemia
pentostatin is a purine analog
20
Q
what is folate?
A
an essential dietary factor from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA
THF is a one-carbon donor
to function as a cofactor, folate must be reduced by DHFR to THF
21
Q
what enzyme do antifolate drugs target?
A
- DHFR
- THF
DHFR reduces folate to THF
THF is a one-carbon donor for DNA precursors
22
Q
what does methotrexate do?
A
inhibits dihydrofolate reductase (DHFR)
DHFR reduces DHF to THF
THF is then used in the reaction:
dUMP –> dTMP via thymidylate synthase
23
Q
what does 5-FU do?
A
inhibits thymidylate synthase so it also has an effect on dividing cells and inhibiting DNA synthesis
normally, dUMP –> dTMP via TS
24
Q
what’s a potential problem with giving someone 5-FU?
A
DPD normally breaks down 5-FU
some people lack DPD enzyme and can have really toxic side effects if you give them 5-FU so you just have to watch out
25
what is the mechanism of action of antifolate drugs?
they inhibit DHFR which results in the depletion of reduced folate (THF)
no THF inhibits de novo purine and pyrimidine biosynthesis and hence, DNA synthesis
26
which phase of the cell cycle do antifolates effect?
they exert their effects in the S-phase of the cell cycle by inhibiting DNA synthesis
27
how are antifolates transported into the cell?
by specific transport proteins RFC & FRP
RFC = reduced folate carrier
FPGS = folylpolyglutamate synthase
then they're metabolized by FPGS to polyglutamated forms to exert cytotoxic effects
28
how does methotrexate enter the cell?
MTX is an analogue of dihydrofolic acid (DHF)
enters the cell through RFC1 = reduced folate carrier 1
once inside the cell, MTX (also known as MTXGlu1 because it's a monoglutamate) is converted into its active polyglutamated forms (MTXGlu2-5) by the enzyme FPGS
the sequential addition of up to four glutamate residues prevents efflux of MTX from the cell
29
what does MTX do?
inhibits DHFR, TS and some other early steps in purine biosynthesis
30
what's the principal site of action for pemetrexed?
inhibition of TS and purine biosynthesis
31
what does DHFR do?
H2-folate --> N5, N10, methylene H4-folate
simplified version:
DHF --> THF
32
what does TS do?
dUMP --> dTMP
33
what are some of the clinically toxic side effects of MTX?
1. myelosuppressive = drops the blood counts and increases risk for infection
2. causes mucositis because all the GI mucosa are rapidly growing so they're very effected by MTX
34
how is MTX cleared?
it's cleared by the kidneys
so you have to reduce its dose if someone is in kidney failure
MTXGlu2-5 are retained in hepatic and renal tissues for long periods of time causing prolonged suppression of THF in these cells
35
what is the MTX rescue drug?
leucovorin
if you give too much MTX, give leucovorin
36
what does leucovorin do?
MTX rescue drug
it's a form of THF that can be readily taken up by cells
if it is administered after overdosing with MTX it can supply THF needed for cell survival until the MTX polyglutamate is finally broken down to free MTX and leaves the cell by diffusion
with high-dose MTX and leucovorin rescue, the patient must be well-hydrated and urine alkalinized, or MTX will precipitate in acidic tubular fluid
37
what do pyrimidine and purine analogs do?
either inhibit nucleotide synthesis or get incorporated into the DNA blocking its function
38
which bases are purines?
adenosine
guanine
*2 rings
39
which bases are pyrimidines?
thymidine
cytosine
uracil
*1 ring
40
capecitabine is an analog to which base?
cytosine
so it's a pyrimidine analog
41
6-merceptopurine is an analog to which base?
guanine
so it's a purine analog
42
5-FU is an analog to which base?
thymines
so it's a pyrimidine analog
43
cladribine is an analog to which base?
adenine
so it's a purine analog
44
fludarabine is an analog to which base?
adenine
so it's a purine analog
45
what disease is fludarabine often used to treat?
chronic lymphocytic anemia
46
which drugs are pyrimidine analogs?
1. capecitabine
| 2. 5-FU
47
which drugs are purine analogs?
1. 6-mercaptopurine
2. 6-thioguanine
3. fludarabine
4. cladribine
5. pentostatin
6. azathioprine
48
what are the side effects of 5-FU?
- myelosuppression if given via bolus
- alopecia
- dermatitis
nausea/vomiting
depends on how you give the drug
49
what are the side effects of capecitabine?
- myelosuppression
- alopecia
- dermatitis
nausea/vomiting
** increased incidence of hand and foot syndrome if you give it via IV/constant fusion
50
what is hand and foot syndrome?
- tingling, burning, or numbness
- redness or swelling
- flaking or peeling skin
- small blisters
- sores or breaks in the skin
- discomfort or pain
51
what's the relationship between capecitabine and 5-FU?
they're both pyrimidine analogs - capecitabine gets converted into 5-FU
capecitabine has to first get changed in the liver and then it gets changed again in the cell
in the cell is where it gets made into 5-FU
52
what happens if you're giving warfarin or cumadin with capecitabine?
capecitabine is being metabolized in the liver, it's competing with the enzymes in the liver
warfarin will increase PT so it's a drug-drug interaction
53
what's the effect of grape juice fruit on p450 system of metabolizing drugs?
it's an inducer of the enzymes
it can effect the metabolism of drugs and increase the toxicity of drugs in the liver
a lot of times, patients want to know about alternative medicine but in this case grapefruit juice can be harmful
54
what is another name for cytarabine?
cytosine arabinoside = Ara-C
it's an antimetabolite that is a **nucleoside! aka it's a base +sugar
55
what disease is Ara-C used to treat?
it's an antimetabolite used in the therapy of AML
AML has a super high doubling time and Ara-C is an antimetabolite so it has a strong effect on rapidly dividing drugs!
56
how does Ara-C enter the cell?
by using the nucleoside transporter hENT1
57
how does Ara-C work?
it competes with the physiological substrate deoxycytidine 5′- triphosphate (dCTP) for incorporation into DNA by DNA polymerases
incorporated Ara-CMP residue is a potent inhibitor of DNA polymerase, both in replication and repair synthesis, and blocks the further elongation of the nascent DNA molecule
58
how do you give Ara-C
continuous infusion
7 days of continuous infusion in combination with anthracycline
must be continuous infusion because 85% of the drug is deaminated by 2 deaminases in the blood stream so it's rapidly degraded
59
what are the side effects of Ara-C?
wipes your bone marrow out...
it's a potent myelosuppressive agent capable of producing acute, severe leukopenia, thrombocytopenia, and anemia with striking megaloblastic changes
but this is kinda what you want when you're treating AML
60
is cytarabine cell cycle dependent?
yes!
it's an antimetabolite so it effects S phase
61
what is azathioprine used for?
it's a purine analog
rarely used to treat cancer, it is mostly used as an immunosuppressant
is a pro-drug, converted in the body to the active metabolite 6- mercaptopurine
62
what is the MOA of azathioprine?
it's a purine analog that's a pro-drug, converted in the body to the active metabolite 6- mercaptopurine
drug metabolism results in the incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity
63
what happens to azathioprine in the body?
azathioprine --> 6-MP --> 6-thioinosinic acid --> 6-thioguanine nucleotides
6-thioinosinic acid inhibits purine synthesis
6-thioguanine nucleotides get incorporated into RNA and DNA
64
what does TPMT enzyme do?
6-MP --> 6-CH3MP
TPMT = thiopurine methyl transferase
5% of the population have decreased/missing amount of TPMT
so without it, if you're giving someone purine analogs like azathioprine, you cam get super toxic levels of the purine analogs
65
what does XO stand for?
xanthine oxidase
involved in purine synthesis, specifically production of uric acid
66
is gout a disorder of purine or pyrimidine synthesis?
purine synthesis
XO enzyme is involved in the production of uric acid
67
what foods do you tell gout patients to avoid?
meat
beer
these foods are high in uric acid
68
what is gout?
uric acid crystals in the joints - usually the toe
it's form of arthritis characterized by severe pain, redness, and
tenderness in joints
pain and inflammation occur when too much uric acid crystallizes and deposits in the joints
69
how do you diagnose gout?
you aspirate and look for uric acid crystals under the microscope
70
what does XO do and which condition is it responsible for?
XO catalyzes 6-MP to 6-thiouric acid (inactive)
so ultimately it's responsible for formation of urate from purines which leads to gout!
71
which drug is used to treat gout? what does it do?
allopurinol
allopurinol inhibits XO which normally catalyzes 6-MP to 6-thiouric acid
72
will a pharmacist warn you of a drug-drug interaction if you order a purine analog drug for a patient who is already taking allopurinol?
if someone is on allopurinol and you want to treat them with a purine analog, you're going to have to reduce the dose of purine analog to avoid drug toxicity
a purine analog, like azathioprine for example, is going to generate a lot of 6-MP
without XO, 6-MP will buildup and cause toxicity
73
what's a side effect of azathioprine?
uric acid buildup
so sometimes when you start to treat cancer with azathioprine which is a purine analog, you can get uric acid buildup
a lot of times then you have to use allopurinol to prevent uric acid buildup
74
how do alkylating agents work?
they cross link DNA and cause damage
they're super reactive and really nasty
they're all immunosuppresing!!
75
what are the sub-classes of alkylating agent drugs?
1. nitrogen mustards
2. nitrosoureas
3. alkyl sulphonates
4. atypical
76
which drugs are nitrogen mustard alkylating agents?
1. mecholrethamine
2. cyclophosphamide
3. ifosfamide
4. melphalan
5. chlorambucil
77
which drugs are nitrosoureas alkylating agents?
1. carmustine (BCNU)
2. steptozocin
3. bendamustine
78
which drug is an alkyl sulphonate alkylating agent?
busulphan
79
which drugs are atypical alkylating agents?
1. procarbazine
2. dacarbazine
3. temozolomide
THESE DRUGS CROSS THE BLOOD BRAIN BARRIER!!!
80
what is temozolamide used to treat?
to treat gliomas, brain cancers
often used in combination with radiation
***it crosses the blood brain barrier!!!!!
81
are alkylating agents cell cycle dependent?
no
they are cell-cycle non-specific drugs
82
what is the MOA of alkylating agents?
they're highly reactive compounds that cross link DNA, RNA and proteins by binding to electron rich areas, specifically, *guanine* in DNA
alkylating agents form highly reactive carbonium ion intermediates which covalently link to sites of high electron density, such as phosphates, amines, sulfhydryl, and hydroxyl groups
their chemotherapeutic and cytotoxic effects are directly related to the alkylation of reactive
amines, oxygens, or phosphates on DNA
83
which types of drugs are cell cycle non-specific drugs?
1. alkylating drugs
2. nitrosoureas
3. cisplatin
4. procarbazine
5. antitumor antibiotics
6. dacarbazine
84
what is the most commonly used alkylating agent?
cyclophosphamide
doesn't have a super high therapeutic index
it has to be activated by the hepatic CYP2B enzymes
in order to get an active byproduct, the liver has to metabolize it to its active byproduct
85
what is a therapeutic index?
has to do with how much bang you get your buck
if you have a precision drug, it has a super high therapeutic index
86
what are the side effects of alkylating agents?
1. neurotoxicity: nausea, vomiting common after nitrogen mustard or BCNU
2. myelosuppressive!! since BM is rapidly producing, they suppress BM which also leads to immune suppression
3. mucosal toxicity: alkylating agents are highly toxic to dividing mucosal cells and to hair follicles, leading to oral mucosal ulceration, intestinal denudation, and alopecia
87
which alkylating agent is the most neurotoxic?
ifosfamide
the most neurotoxic agent of this class and may produce altered mental status, coma, generalized seizures, and cerebellar ataxia
88
what diseases can alkylating agents lead to?
busulphan & cyclophosphamide can cause pulmonary fibrosis and veno-occlusive disease
this will also lead to SIADH
alkylating agents can also lead to male/female reproductive damage
89
what are the platinum coordinating complexes?
1. cisplatin
2. carboplatin
3. oxaliplatin
90
what is the MOA for platinum drugs?
they're part of the alkylating agents superfamily
they bind to nucleophilic sites on DNA and cause DNA damage (both intra and interstrand covalent links)
inside the cell, chloride is replaced by water and the drug is activated. High concentrations of chloride stabilize the drug reducing its cytotoxicity
91
are platinum coordination complexes cell specific?
no
92
what are the side effects of cisplatin?
nephrotoxicity and ototoxicity
CNS toxicity is more severe than other AA
marked nausea and vomiting, peripheral neuropathy
myelosuppression
93
what cancers is cisplatin useful for treating?
very useful for a variety of solid tumors:
testicular, ovarian, head and neck, and lung cancers
94
what's the difference between cisplatin and carboplatin?
cisplatin is very kidney toxic
when you get cisplatin you have to pre and post hydrate
but carboplatin is much more myelosuppressive
95
which drugs are vinca alkaloids?
1. Vincristine (most common, most myelosuppressive)
2. Vinblastine
3. Vinorelbine
96
what do vinca alkaloids do?
inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the mitotic spindle
they bind to β-tubulin and prevent its interaction with ɑ-tubulin
they arrest the cell in metaphase which stops cell division and leads to cell death
97
are vinca alkaloids cell cycle specific?
yes
they arrest the cell in metaphase which stops cell division and leads to cell death
98
vinca alkaloids are active in which phase of the cell cycle?
M phase
99
what is vinblastine most used for?
testicular cancer and HL
vinblastine is myelosuppressive!
vinBlastine = Bone marrow suppression
100
what is vincristine most used for?
vincristine with prednisone is very useful for childhood leukemias
vincristine is neurotoxic!
viNcristine = Neurotoxic
101
which drugs are taxanes?
1. paclitaxel
| 2. docetaxel
102
what are taxanes?
hyper-stabilizes microtubule structure = freezes them
they bind to the β subunit of tubulin ,the resulting microtubule/taxane complex does not have the ability to disassemble
this adversely affects cell function because the shortening and lengthening of microtubules is necessary for their function
this results in apoptosis of cancer cells
103
what phase of the cell cycle do taxanes effect?
M phase
microtubules
104
when do you have to watch out for the dose of taxanes?
if there's hepatic dysfunction
105
what are taxanes used to treat?
they have become central components of regimens for treating metastatic ovarian, breast, lung, GI, genitourinary, and head and neck cancers
106
what are the side effects of taxanes?
myelosuppression
neuropathy!! neurons rely on microtubules
107
what are topoisomerase?
DNA topoisomerases are nuclear enzymes that reduce torsional stress in supercoiled DNA
this allows for selected regions of DNA to become sufficiently untangled and relaxed to permit replication, repair, and transcription
type I: cuts one strand
type II: cuts two strands
108
what phase of the cell cycle do topoisomerase I inhibitors effect?
S phase
***topoisomerase II are NOT cell cycle dependent
109
which drugs are topoisomerase i inhibitors?
irinotecan
topotecan
110
what do topoisomerase I inhibitors do?
the initial cleavage action of topoisomerase I is not affected but the re-ligation step is inhibited
this leads to the accumulation of single-stranded breaks in DNA
the collision of a DNA replication fork with this cleaved strand of DNA causes an irreversible double-strand DNA break, ultimately leading to cell death
111
what are some side effects of topoisomerase I inhibitors?
myelosuppression
diarrhea
112
what are anthracyclines?
they inhibit topoisomerase II
they to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission
they are NOT cycle dependent!!
113
which drugs are anthracyclines?
1. doxorubicin
2. daunorubicin
3. mitoxantrone
114
are anthracyclines cell cycle dependent?
no!
they act at multiple phases during the cell cycle
115
what is doxorubicin?
anthracycline/topoisomerase II inhibitor
anticancer drug with major clinical activity in several cancers
116
what's the major side effect with doxorubicin?
cardiotoxicity!!
creates ROS that damage the heart
acute: arrhythmias
chronic: digitalis-resistant congestive heart failure; lifetime dose dependent - 20% of patients receiving 550 mg/m2
117
what is etoposide?
inhibitor of topoisomerase II
118
what is etoposide used to treat?
primarily used for treatment of testicular tumors, in combination with bleomycin and cisplatin, and in combination with cisplatin and ifosfamide for small cell carcinoma of the lung
119
what are the side effects of etoposide?
it's leukemogenic and may cause acute nonlymphocytic leukemia in children
myelosuppression
120
what is bleomycin?
DNA cleaving antibiotic
water soluble, basic glycopeptide with a core of either Fe2+ or Cu2+
it's metabolized by hydrolases found in almost all tissues except, skin and lungs
121
what are the side effects of bleomycin?
cytotoxicity results from its ability to cause oxidative damage to the deoxyribose of thymidylate and other nucleotides, leading to single- and double-stranded breaks in DNA
damaged cells accumulate in the G2 phase of the cell cycle
**toxicity to skin and lungs
122
what is bleomycin used to treat?
highly effective against germ cell testicular cancer and HL
123
is bleomycin cell cycle specific?
yes
G2 and M phases
124
what is the skin toxicity side effects seen in bleomycin?
hyperpigmentation, hyperkeratosis, erythema, and even ulceration
rarely, patients with severe skin toxicity may experience Raynaud's phenomenon
125
which groups of drugs cause neuropathy?
taxanes and vinca alkaloids
anything effecting the microtubules because neurons rely on microtubules
