Anti-Neoplastics Flashcards
(158 cards)
1
Q
What are the mechanisms that anticancer drugs act on?
A
1) damage DNE
2) Inhibit synthesis or funtion of DNA
3) ACtion on Mitotic Spindle
4) targeted DRUGS (MABs, NIBs, and mTOR inhibitors)
2
Q
Cell cycle spefic drugs
A
most effective in the certian phases of the cell cycle
3
Q
cell cycle NON specific
A
their targets are present in both the cell cycle and resting cells
4
Q
What are alkylating agents?
A
- moiety bound to DNA to stop cell cycle
- Nitrogen mustards
- Alkyl sulfonates
- Nitrosoureas
- Aziridines
- Antibiotics
- Platinum drugs
- Triazenes
- Hydrazines
5
Q
What is adjuvant therapy?
A
given to activate the immune response after surgery
6
Q
What is neoadjuvant therapy?
A
given to debulk the tumore, and remove tumor cells from the inffected site
7
Q
What is Tumor lysis syndrome (TLS)
A
a multi-factorial process,
- the lysis of tumor cells relases purine nucleic acids K+ and P
- get renal saturation due to elimination
- uric acid deposites with calciump
- volume depetion, tubular obstruction, cytotoxic chemotherapy
8
Q
How do you manage TLS?
A
hydration!!!!
allopurino to prevent uric acid formation
Rasburicase to degrade uric acit to water soluble allantoin for elimination
9
Q
What are teh bischloroethylamine alkylating agents?
A
cyclophosphamide ifosfamide merchlorethamine melphalan chlorambucil
10
Q
What are the mechanisms of the bischloroethylamine alkylating agents?
A
- transfer alkyl group ot DNA
- N7 guanine
- ss or ds DNA cross-linking DNA modified
- Resulting in miscoding; strand breakage via guanine excision
11
Q
What are the resistance mechanisms of the bischloroethylamine alkylating agents?
A
-v uptake
v activation
^ inactivation (conjugation) of reactive moiety (^rate& capactity) or ^ repair of DNA miscodes
12
Q
What are adverse effects of the bischloroethylamine alkylating agents?
A
- does-related toxicites
- direct vesicant action (avoided where orally acitve)
- eps toxic to rapidly dividing cell populations (bone marrow, GI, Reporductive systems, alopecia)
- N/V (use 5HT3 antagoinist)
- CNS(ifosfamide– chloroactealdehyde)– altered mental status etc
- Lungs (ALL ALKYLATING AGENTS esp cyclophosphamide, chlorambucil, melphalan
- — fibrosis, dyspenea, cyanosis, pulmonary insufficiency
- carcinogenity- lekemias and solid tumors (secondary malignacies)
- Renal failure (cyclophosphaamide and ifosfamide)
- Urotoxicity/bladder tumore (acrolein released by cyclophosphamide and ifosfamide)
- – sever hemorrhagi cycstitis (MENSA prevents)
13
Q
What is Mesna and what does it prevent?
A
a phophylatic chemoprotectant from hemorrhagic cystitis
-IV/oral
14
Q
What does cyclophosphamide do and when is ti used?
A
total immune system ablation
used for allogenic stem cell transplantation, and RA
15
Q
What are the alkyl sulfonates?
A
Busulfan
16
Q
What are the toxicities, of busulfan?
A
myelosuppression, at conventional doses
pulmonary fibrosis
GI damage
Veo-occlusive diseasze of the liver, increased by coincident cyp inhibitors
asthenia and HYT resembing addison’s disease
17
Q
What are the Nitorsoureas?
A
Carmustine and Lomustine (both akylators)
-carmustine decompostition products carbamolyate proteins– inhibit DNA repair
18
Q
Is cross resistance with other alkylating agents comon for hte nitrosoureas’?
A
NO!!
19
Q
What is the distributation of the nitrosoureas’?
A
enter CNS in measurable concentrations b/c hygly lipophilic & non-ionized at physicologic pH
20
Q
What are the toxicities for the nitrosoureas’?
A
thromobcytopenia, leucopenia, N/V, administration site rxns
pulmonary fibrosis
endocrine dysfunction with brain irradiation
– hyperprolactinemia, and hypthyroidism (v throxin T4)
-encephalopathy and seizures
^ transminases, alkalin phosphatase, and hyper bilirubinemia
21
Q
What is thiotepa and what are its toxicities?
A
a polyfunctional aziridine alkylator
- forms intersrand cross-links of DNA
- lipophilic (IV, IVe, or IC)
- Toxicities: myelosuppression, neurooxic, injection site rnx, dysuria, urinary urgency, urinary retention, chemical or hemorrhagic cystitis
22
Q
What is mitomycin and what does it do?
A
a bioreductive alkylating agent -metabolically activated under reducing contictions (hypoxic solid tumor) -superoxide free radical generation -bone marrow suppression (slow recovery) Injection site rns (hemolytic anemia)
23
Q
What are the platinum drugs?
A
cisplatin, carboplatin, oxaliplatin
24
Q
What does cisplatin do?
A
-intrastand DNA links with N7 guanine,
The DNA relication and transcription interrupted (breaks and miscoding, P53/checkpoint proteins -> induction of apoptosis)
25
What are the toxic effects of cisplatin?
nephrotoxic!!! (amifostine a cytoprotective agent!!!)
Ototoxicity (hearing loss)
mild to mod- myelosuppression
marked N/V (ondansetron + steroids + aprepitant (NK-1 antagonist))
porgressive peripheral, motor & sensory neuropathy
26
What is Dacarbazine?
a triazine DNA methylating agent (O6 guanine)
| resistance due to removal of methyl groups form teh O6 guanine bases by AGT
27
What are the toxicites of Dacarbazine?
Myelosuppression; leukopenia, thrombocytopenia,
| N/V
28
What are the DNA methlyating agents?
Trazewnes and Hydrazine
29
What is procarbazine and what is its mechanism?
a highly reactive DNA methylaor via CYP activation -- causes damage via creaks and translocations
30
What is the resistance to procarbazines?
rapid when use as a single agent due to guanine repair via guanin-O6-alky transferase, and also lacks cross-resistance with other mustratd-type alkylators
31
What are the adverse/ toxicities seen with procarbazine?
```
leukopenia and thromobytopenia
-Mild N/V
-Weak MAO inhibitor , hypertensive DDrns
-Disulfiram-like actions (alcohol ingestion to be avoided)
potent immunosuppressive
```
32
What are the antimetabolites?
- folic acid analogs
- pyrimidine analogs
- purine analogs and related inhibitors
33
What are the folic acid analogs?
Methotrexates
34
What are the pyrimdine analogs?
Fluorouracil (5-FU)
capecitabine
Cytarabine
Gemcitabine
35
What are the purine analogs and related inhibitors?
Pentostatin
cladridine
Fludarabine
36
What is methotrexates mechanism?
a DHFR inhibitor, adn is trapped in cell due to polyglutamated
37
What is important about the methotrexate mechanism, due to THF?
methotrexate deplets the THF from all cells and thus must use Leucovorin to rescuce the cells that are not tumor cells,
38
What are the other methotrexate analogs?
Pemetrexed
| Trimetrexate
39
What are the toxicites of methotrexate?
GI, N/V, abdominal distress
- Bone marrow, anemia, lymphoproliferative disorders
- weak acid; hydrate adn alkaliinize urine
- pneumonitis
- anemia in RA or psoriasis (MTX and 5-FU)
40
What are the resistance mechanisms for MTX?
V uptake/^ efflux; V polyglutamation
| -^ DHFR enxyme levels & or modified structures
41
What is 5FU mechanism?
Inhibits DNA synthesis by "thymineless death" (FdUMP)
incorporated into DNA to inhibit synthesis and function (FdUTP)
interference with mRNA translation (FUTP)
42
What are the resistance mechanisms for 5-FU?
V activation of 5-FU; muation of TS; upregulation of TS (feedback b/c unbound enxyme inhibitis own mRNA)
43
What are the toxicites of 5-FU?
Acute chest pain (ischemia)
myelosuppression, anemia, mucositis, diarrhea,
-Hand and foot syndrome!!! -- peripheral neuopathy!!!!!!!
44
What is the interaction with leucovorin?
5-FU: increase formation of TS complex and enchances the response to 5-FU
MXT: given as a THF rescue
45
What is Capecitabine, and how is it similar/differnt from this durg?
a pre-drug of 5-FU
| -similar toxicities!!! (hand-foot syndrome ^ in frequency)
46
what is the mechanism of cytarabine?
a antimetabolite, pyrimide analog
- converted to ARA-CTP
- -- the 2'hydroxyl hinders 3-D bond rotation; interferes with base stacking
- inhibition of chain elongation (leads to shortened DAN strands)
- Multiple DNA strand duplications (increase recombination possibilites)
47
What are the resistance and toxicites for cytarabine?
Resistance: V cellular uptake; decreased ARA-C conversion to ARA-CTP; or increased ARA-CTP to ARA-UMP (inactive)
Toxicitiy: potent myelosuppressive agent; severe leukopeina, thromovytopenia, and anemia, megaloblastic changes
-GI, and noncardiogenic pulomary edema
48
What is Gemitabine?
has an additional bp, and the repair is more difficult
-better penetration/retention; affinity for dinase
Toxicity is myelosuppresion, flu like symptoms and ^ liver transaminases
49
What is mercaptopurine's resisances?
- v or complete lack of HGPRT
- ^alkaline phosphatase activity
- v drug uptake and ^ efflus
- altered enxyme sturcture
- altered recognition of DNA breaks
50
DDI with mercaptopurine?
Allopuinol!!! must reduce does to avod excessive toxicity!!!
51
What is the benifit of TPMT genotyping with mercaptopurine administration?
if low TPMT leves will have to use ^ does of drug to be benificial
52
What is thioguanine?
similar mechanism of action as 6MP (RNA & DNA synthesis inhibition; incorporation of thio-nulecotide into RNA and DNA), with similar resistance mechanisms
53
What is the mechanism of fludarabine & cladribine?
-rephosphorylated intracellularly ot acitve triphosphate derivative (resistance; v enxyme activeity -- not P)
-inhibits DNA synthesis & ribonucleotide reductase
-activeates apoptosis (acive agains indolent disease
they have long lasting effects
54
What are the natural products?
Plant alkaloids and mold products
55
What are the vinca alkaloids?
Vincristine
Winblastine
Vinorelbine
56
What are the amptothecin analgos?
Topotecan
| Irinotecan
57
What are the podophyllotoxins?
Paclitazel
| Docetaxel
58
What are the anthracyclines?
```
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Mitoxantrone
```
59
What are the Bleomycins
Bleomycin
60
What are the actinomycins?
actiomcin D
61
What are the asparaginase?
asparaginase
62
What is extravasataion toxicity?
Excape of drug from vascular causeing excessive toxicity (localized) and loss of tissue which can be devilitating and plastic surgery to correct
63
What is the mechanism of the vinca alkaloids?
they bind specifically to b-tublin and block tubulin (alpha and beta) polymerization
-this arrests cells in metaphase (apoptosis)
64
What is the resistance of vinca alkaloids?
-P-glycoprotien, MRP, BCRP
--- b-tubulin mutations (the binding site)
efflux protein actiators
65
What is the toxicites for the vinca alkaloids?
neurotoxicity--- due to the presance of microtubules in the CNS
- allopecia
- leuokpenia not with vincrstine
- peripheral neuropathy!!! (tingling in hands and feet)
66
What is the relationship b/ taxols adn vinca alkaloids?
both act on the b-tublin
Taxols- prevent disassembly
vinca alkaloids- prevent polymeriation (loss of activity)
and they bind to specific stide on the b-tubulin (also colchicine in tx of gout)
67
What is the mechanism of camptothecin analogs?
- stabilize DAN-topo I cleavable comoples
| - - ssDNA breaks and dsDNA breaks
68
what are the resistance mechanisms of irinotecan and topotecan?
- G2 arrest correlates with v drug sensitivity
| - invitro: ^ efflux (p-gp, MRP) mutation or ^ expression of topo-I or topo-II
69
What is the difference in excreation of irinotecan and topotecan?
Irinoteacn: hepatic metabolism (UGT polymorphisms impact clinical use-- V conjugation=^ neutropenia)
-- with severe toxicity in pts with Gilbert syndrome
Toptecan: renal elimination (dose adj.)
70
What are the toxicites of topotecan?
neutropenia +/- thrombocytopenia
| -cuscositis and diarrhea, N/V elevated hepatic enzyems
71
What are the toxicites of irinotecan?
dose limiting diarrhea!!!
- 24 hr: Loperamide effective except in sever cases, rarely fatal
- myleosuppression: anemia, leukopenia, neutorpenia
- N/V, nucositis, alopecia
- elevation in hepatic enxymes
72
What is the mechanism of Etoposide and teniposide?
they complex with topo-II and DNA
73
What are the resistacne mechanisms of etoposide and teniposide?
^ efflux; mutation or v topo-II (P53 mutation)
74
What are the differing routes of admistration and toxicites, with eliminations for the Topo-II inhibitors?
Etoposide- oral, renal elimation ; dose adjust; myelosuppression and alopecia
Teniposide- IV; extensive metabolism; myelosuppression & N/V
75
What is Paclitaxel and Docataxel's mechanisms?
bind to b-tubulin and antagonize disassembly
76
What are the resistance mecaninsme for the taxols?
efflux; mutation of targert
77
What is important about paclitazel (IV taxol)?
cermaphor casues hypersensitivity; and can be treated by prophylactic antihistamine and steroids
78
What is improtant about Docataxel(IV docetaxel)?
polysorbate 80 is disolving and has a lower incidence of hypersensitivity
79
how are the taxols metabolized?
extensivly via CYP metabolism (paclitaxel clearance is not dose linear -- cremaphor)
80
What are the toxicites for the taxols?
```
Paclitaxel: (bone marrow suppression, myalgias & stokcing-glove sensory neurophathy, mucositis)
Docetazel toxicity (more severe, but short-lived, neutropenia, peripheral/ pulmonary edema; progressive with duration -- prophylactic oral dexamethasone)
```
81
What are the important mechanism of hte Anthracyclins?
1) intercalate with DNA, affecting transcription and replication
2) ceomplex with TOPO-II and DNA
3) free radicals from semiquinone
82
What are the resistance mechanisms of the antracyclines>?
^ efflux
^ glutathion peroxidase (free radical scavenger)
v topo or mutation
^ repair efficiency
83
What are the toxic effects of aunorubicin, Doxorubicin, Epirubicin and Idarubicin?
myelosuppression stomatitis, alopecia, GI disturbances (extravasational necrosis)
***Acute (reversible): tachycardia, arrhythmias, hypotension,v ejection fraction, troponin-T release
Chronic (irreversible) CHF -- max dose 500mg/m2 ( may requrie a hrt transplant)
Protection with dexrazoxane, iron chelatin agnet
84
What drugs produce red urine?
any systemic drugn (danunorubicin, doxorubicin, epirubcin, idarubicin)
85
What drug produces blue urine?
Mitoxantrone
86
What is mitoxantrone's mechanism of action?
intercalates DNA and inhibitos TOPO-II (ss and ds breaks)
87
what is mitoxantrone's toxicity?
myelosuppression, cardiotoxicity, mucositis, stomatitis, alopecia
Cardiotoxicity (Dox/Dauno similarities)
88
What drug-Fe complex oxidizes deoxyribose of thymidylate adn other nuclotides?
Bleomycin,
| ss and ds DNA breaks
89
What is the resistance to Bleomycin?
degradation by specific hydrolase (low activity skin & lung)
| v uptake, adn ^ rtepair, ^ inactiavactivation
90
What are the toxicities to Bleomycin?
Pulomary toxicity, dry cough--> fibrosis
hyperpigmentation, hyperkeratosis, erythema, ulceration (low activity of degenrative hydrolase in these areas)
91
What druge intercalates DNA (adj G-C base pairs)
AntinomycinD
92
What type of DNA breaks doe Actinomycin-D do?
ssDNA via fre-radical and TOPO-II action
93
What are the toxic effects of Actinomycin-D
Pancytopenia, anorexia, N/V
Mucositis, Diarrhea, alopecia, extravasation necrosis
-erythema, desquamation, inflammation and pigmentation in areas previously or concomitantly, x-rayed (skin toxicity)
94
What does L-Asparaginase do?
and enzyme form E. Coli
that converts Asp--> Aspartic acid adn ammonia
helps to stop lymphid cancer
95
What is the resistacne to L-asparaginase?
increase asparagin synthatse
96
What can L-Asparaginase caseue?
Pancreatitis: necrotic/inflammatory
| Has a potentiallyl fatal hypersentitivy
97
What are the Miscellaneous Agents?
Hydroxyurea,
| Thalidominde
98
What are the differntiating Agents?
Tretinoin
99
What are the immunosuppressants?
Glucocorticoids
| Dexamethasone
100
What are the EGFR antibodies?
Gemtuzumab
Tratustuzumab
Cetuximab
Panitumumab
101
What are the VEGF antibodies
Bevacizumab
102
What are the antibodies to CD20?
Rituximab
| Ofatumumab
103
What are the antibodies to CD52
Alemtuzumab
104
What are the radiolabeled drugs?
Ibritumumab
| Toistumomab
105
What are the TKIs?
Imatinib Dasatinib
106
Waht are the EGFR TKIs?
Gefitinib
Erlotinib
Lapatinib
107
What are th eBCR-ABL TKIs?
Imatinib
Dasatinib
Nilotinib
108
What are the VEGF TKIs?
Suntiinib
Sorafenib
Pazopanib
109
What are the proteosome inhibitors?
Bortexomib
110
What are the mTOR inhibitors
Sirolimus
Everolimus
Temsirolims
111
What is Hydroxyureas?
a oral free radical scavanger
stops at the rate limiting step in DNA synthesis, and prevent DNA replication and cell synthesis
catalytic center of ribonucleotide reductase subunit
112
What are the resistance mechanism for hydroxyurea?
upregulation of reductase
113
What is hydroxyurea used as?
a mylosuppressive or radiation sensitizer
114
What is thalidomide, an what did it previously get used for?
- is an anti-cancer drug
- -inhibits tumore cell proliferation
- -inhibits tumor cell adhesion to stroma
- - inhibitos angiogenesis
- -Enhances NK cell activity
- used to be used for deditive in pregancy
115
What are the toxicities of Thalidomide or lenalidomide?
tx-emergent peripheral sensory neuropathy, sedation, constipation
116
What are the adrenocorticosterodis?
prednisone, dexamethasone
117
What is the mechanism of Tretinoin?
disrupts gene and promotes differnetiaon
| is a teratogen so avoid during preg...
118
What is retinoic acid syndrom?
characterized by fever, dyspenea, weight gain, pulmonary inflitarates, and pleural or pericardial effusions
119
What are the targeted therapies?
cell surface recptor antibodies
receptor tyrosine kinase inhbitors
mTOR inhibitors
PI3L inhbitors
120
What are the cell surface receptor antibodies?
- EGFR
| - VEGF
121
What are the RTKIs?
- multi-receptor
| - single-receptor
122
What does trastuzumab bind too and what does is cause?
The ErbB2/.ErbB3 complex disruption and casues Ligand- INdependent signaling (AKT & PI3 activation)
123
What does Pertuxumab bind too and what does it cause?
Binds to ErbB2 ErbB1/3/4 complex adn causes Inhibiton of Lignad-Dependent signaling
124
What does Iapatinib bind too adn what does it cause?
binds to ErbB2 ErbB1/3/4 and causes inhibiton of Ligand-dependent adn Ligand- independent signaling (inhibiton of ErbB1/2 TK activity)
125
What is rituximab's mechanisms of cytotoxicity?
directly
ADCC
Complment activation
126
Drug:
| Gemtuzumab
Mechanism:
apoptosis, ADCC
EGFR-2 Her-2/neu
127
Drug: Trastuzumab
Mechanism:
Aoptosis, ADCC
EGFR-2 Her-2/neu
128
Drug: Cetuximab
mechanism:
Apoptosis, ADCC
EGRF-1, Her-1
129
Drug: Panitumumab
mechanism:
Apoptosis, ADCC
EGRF-1, Her-1
130
Drug: Bevacizumab
Mechanism; anti-angiogenesis, neovascularization VEFG BLOCK
131
Drug: Rituximab
Mechanism
apoptosis, ADCC, CDC
CD-20 targeted
132
Drug Ofatumumab
Mechanism
Aoptosis, ADCC, CDC
CD-20 targeted
133
Alemtuxumab
mechanism:
Apoptosis, ADCC, CDC
CD-52 targeted
134
Ibritumomab Tiuxetan
Mechanism:
Apooposis, weak phagocytosis, irradiation
CD-20targted
135
Tositumomab
Mechanism: Apoptosism, ADCC, CDC, irradiation
| CD-20 targeted
136
That are the EGFR TKIs?
Gefitinib, Erlotinib (ErbB1, HER-1)
| Lapatinib (ErbB1, HER-1 & ErbB2, HER-2)-- has QT prolongation
137
What are the BCR-ABL TKIs?
Imatinib adn Dasatinib
| Nilotinib-- QT prolongation
138
What are the mechanisms of resistance to oral TKI?
decreased intracellular drug levels
increased plasma protein binding
MDR-1 (p-gp) mediated efflux
genomic amplification of kinase
clonal evolutiono f kinase-independent mechanism
mutation of ATP-binding site affecting drug binding or kinase activity (highly conserved site)
139
What are the VEGF TKIs?
Sunitinib, Sorafenib, pazotanib-- prolonged QT interval
140
What are the mTORS?
sirolimus
everolimus
temsirolims
141
What are the interferons?
casue muscle ache and fever
| interferon-alpha-2a, promote cell cycel arrest in Go, induces apoptosis induces immunological respone (CTLs and NK)
142
What is Bortexomib's pathway?
works on the NEMO pathway to prevent removal of IKB so NFkB cant activate cytokines
143
What are the 3 factors influencing chemotherapeutic responses?
1) pharacokinetics
2) tumor-cell specific
3) tumor microenviornment
144
What are the possible resistance mechanisms?
Antineoplastic Agent
1) decreased uptake of drug into cancer cell
2) failure to be metabolixed into pharmacologically active moiety
3)Enhanced metabolism to inactive products
4) Increased active transport of drug out of cancer cell
DNA, Target Enzyme, or othe rMacromolecule
1) repair of drug-induced DNA damage
2) gene amplification or increase gene transcription leading to an increased amount of target enzyme with in the cancer cell
3) reduced ability of drug to bind to target enxyme
4) increased levels of sulfhydryl scavengetrs
5) altered concentration of target proteins
6) increased expressionon antiapoptotic genes like bcl-2
145
Oncology agent:
| 1) tumor lysis syndrome
Concurrent Agent:
1) Allopurinol, Rasburicase
to reduce uric acid level,; renal protective
146
Oncology agent:
| 2) cyclophosphamide, ifosfamide
Concurrent Agent:
| 2) Mesna (protective against acrolein product)
147
Oncology Agent: Cisplatin
Concurrent Agent: Amifostine (cytoprotection)
148
Oncology Agent: MTX
Concurrent Agent: Leucovorin (metabolic resuce)
149
Oncology Agent: 5-FU
Concurrent Agent: Leucovorin (enhanced action)
150
Oncology Agent: 6-MP
Concurrent agent: Allopuniol (CAUTION: INCREASES TOXICITY!!!!!)
151
Oncology agent: Antracyclines
Concurrently Agent:Dexroxazone (Fe chelator; reduced cardiotoxicity)
152
Oncology agent: Bone metastases
Concurrent agent: pamidronate, zoledronate (reduced bone pain and fractures)
153
What drugs are shoulw to have CV morbidity (CHF and LV dysfunction)?
Anthracyclines adn Mitoxantrone
154
What causes Hypertension?
Bevacizumab, sorafenib, sunitinib
155
What causes edema
Imatinib
156
What causes QT prolongation or TP?
Sorafenib, Sunitinib
157
What casues thrombo-embolic complications?
Bevacizumab, Thalidomide, Estramustine
158
What are the substrates for energy dependent efflux pumps?
```
cisplatin
boxorubicin
daunorubicin
etoposide
paciltaxel
teniposide
topotecan
vinblastine
```
