Antimitotics, Alkylators, Platinums Flashcards
(86 cards)
1
Q
Which drugs make up the vinca alkaloids?
A
- vincristine
- vinblastine
- vinorelbine
2
Q
What are the major differences btw. the vinca alkaloids?
A
- Differ in their tubulin-binding affinities: VCR > VBL > VRL
- AEs: VCR is less myelosuppressive than VBL. VCR is more likely to cause peripheral neuropathy or GI effects such as ileus.
- VCR and VBL: decrease the shortening rate and increase the time microtubules spend in an attenuated state to a much greater extent
- VCR and VBL= natural, VRL= synthetic
- VCR- possesses formyl grp, VBL= possesses methyl grp
3
Q
Describe the microtubule structure.
A
Composed of tubulin (heterodimer= alpha and beta)
- assemble into linear protofilaments (13 in each MT)
- arrange into a helix with one turn
4
Q
What is meant by microtubule treadmilling?
A
It occurs when one end of a filament grows in length while the other end shrinks resulting in a section of filament seemingly “moving” across a stratum or the cytosol.
- Two ends (treadmilling)
minus= alpha tubulin exposed= net shortening (slow assembly)
plus= beta tubulin exposed= net elongation (fast assembly)
5
Q
Which chemotherapeutic drugs have the following MOA?
Bind rapidly and reversibly to tubulin causing inhibition of microtubule assembly
A
vinca alkaloids
6
Q
What phase of the cell cycle do vincas block at?
Where does most damage occur and in which phase do the cells die?
A
metaphase/anaphase in mitosis
Most damage occurs in S phase and cells die in M phase
7
Q
At higher concentrations, what effects do the vincas have on the microtubules?
What about at lower concentrations?
A
Higher concentrations= binds along side of MTs leading to disintegration
Lower concentrations= inhibits assembly of MT
8
Q
T/F: Vinca alkaloids are considered radiosensitizers. Why?
A
True: due to the ability to block cell cycle in G2/M phase
9
Q
T/F: Vinca alkaloids are angiogenesis inhibitors. Why?
A
True: they block endothelial cell proliferation, chemotaxis, and spreading of fibronectin
10
Q
Choose the correct answers from below that describe other effects of MOA that vincas have beyond what you know for their cytotoxic effects on cancer.
- decreased intracellular transport of AA
- disrupt interphase MTs and DNA synthesis in non-diving cells
- inhibit neutrophils, proliferation of lymphs and fibroblasts
- inhibit DNA/RNA/protein synthesis
- Disrupt cell membrane integrity
- induces expression of TNA-alpha
- Inhibit glycolysis
- Alter intracellular movement of organelles
- inhibits secretory functions
- Maintain structural integrity of platelets
A
- decreased intracellular transport of AA
- inhibit DNA/RNA/protein synthesis
- Disrupt cell membrane integrity
- Inhibit glycolysis
- Alter intracellular movement of organelles
- Maintain structural integrity of platelets (VCR used for ITP)
11
Q
What are the major mechanisms or resistance to the vincas?
A
- all effected by MDR (Pgp/MDR1)
- Alterations in apoptotic pathway
- Alterations in alpha and beta subunits of tubulin (increases MT stability)
- Increased expression of microtubule associated proteins (promote MT assembly and hyperstability)
12
Q
What is the major dose limiting toxicity for the vinca alkaloids?
A
VCR- neurotoxicity
VBL, VRL- myelosuppression
13
Q
What is the major DLT for VCR besides myelosupression?
A
Neurotoxicity: mixed sensory and motor peripheral neuropathy
14
Q
Which of the vincas has been linked to SIADH?
A
vincristine
15
Q
Which of the vincas is most known to cause ileus in veterinary patients?
A
vincristine
16
Q
What is the form of metabolism and also excretion for the vincas?
A
extensive hepatic metabolism and biliary/fecal excretion
17
Q
What is the strategy for a vinca extravasation?
A
- Aspirate drug out
- Warm compress
- Can inject warm saline for dilution
- Can inject hyaluronidase- breaks down hyaluronic acid in soft tissue, allowing for dispersion of the extravasated drug
18
Q
What is the drug interaction that occurs with VCR and Elspar?
A
Elspar reduces hepatic clearance of VCR
19
Q
What is the drug interaction that occurs with vincas and methotrexate?
A
Vincas block efflux of methotrexate leading to increased intracellular accumulation
20
Q
What is the reaction of cytochrome p450 inhibitors and vincas?
A
they increase toxicity of vinca alkaloids
21
Q
What are the drugs that make up the taxanes?
A
- Pacilitaxel
2. Docetaxel
22
Q
Which chemotherapeutic drugs have the following MOA?
- bind to polymerized tubulin along the length of the MT at the N-terminal beta subunit
- inhibit microtubular disassembly, which then prevents the normal growth and breakdown of microtubules that is required for cell division
A
taxanes
23
Q
How does the MOA of vincas and taxanes differ?
A
taxanes: promote elongation which stabilizes the mitotic tubule against disassembly and enhances polymerization; inhibits dynamic reorganization of MT network
vincas: work by the disruption of protein-protein interactions, most specifically by disrupting the interaction between α- and β-tubulin; prevents assembly
24
Q
Describe the difference in where the vincas and the taxanes bind to the MT?
A
vincas: bind to the ends of microtubules
taxanes: N-terminal β-subunit; bind to the interior surface
25
At higher concentrations, what effects do the taxanes have on the microtubules?
What about at lower concentrations?
Higher: inhibit MT dissasembly
(induces a modest increase in MT length at the plus ends)
Lower: inhibit dynamic instability and treadmilling
(reduces the rate and extent of MT shortening at their plus ends)
26
What phase of the cell cycle do taxanes block at?
Which of the phases of the cell cycle is the most specific?
metaphase/anaphase of mitosis
Mainly M phase, but also blocks G0/G1 phase
27
MT disruption by the taxanes will lead to induction of which cell cycle regulators leading to a downstream affect of cell disregulation and therefore apoptosis?
p53 and inhibitors of CDKs which leads to cell cycle arrest in G2/M and then apoptosis
28
T/F: The taxanes are considered radiosensitizers?
True
29
# Choose from below other effects of MOA that taxanes have beyond what you know for their cytotoxic effects on cancer.
1. decreased intracellular transport of AA
2. disrupt interphase MTs and DNA synthesis in non-diving cells
3. inhibit neutrophils, proliferation of lymphs and fibroblasts
4. inhibit DNA/RNA/protein synthesis
5. Disrupt cell membrane integrity
6. induces expression of TNA-alpha
7. Inhibit glycolysis
8. Alter intracellular movement of organelles
9. inhibits secretory functions
10. Maintain structural integrity of platelets
1. disrupt interphase MTs and DNA synthesis in non-diving cells
2. inhibit neutrophils, proliferation of lymphs and fibroblasts
3. induces expression of TNA-alpha
4. inhibits secretory functions
30
T/F: Unlike the vincas, taxanes do not have the ability to disrupt endothelial cells and inhibit angiogenesis.
False
31
What is the metabolism and excretion of the taxanes?
metabolized by cytochrome p450 in the liver and excreted in the bile/feces
32
What are the mechanisms of resistance of the taxanes?
1. MDR
2. alteration in tubulin binding sites
3. decreased apoptosis due to altered cell signaling
33
Why is the oral bioavailability of taxanes poor?
1. high Pgp on enterocytes
| 2. intestinal cytochrome p450 enzymes
34
Which drug can be administered with taxanes in order to alter the Pgp/cytochrome p450
cyclosporine
35
What are the major DLTs of paclitaxel?
1. cardiotoxicity
- transient asymptomatic bradycardia most common
- other arrhythmias can occur
- long term--> cardiac dysfunction
2. peripheral neuropathy
3. Rarer effects:
hepatotoxicity, acute pneunomitis, nail disorders
36
What are the major DLTs of the taxanes?
1. neutropenia (3-5 day nadir)
| 2. Type I hypersensitivity
37
What are the major DLTs of docetaxel?
1. Edema and 3rd spacing (increased capillary permeability)
2. PPDE- palmar plantar erythrodysethsia
3. Nail bed changes- brown coloring, ridging, loss of nail plate
4. Neurotoxicty: paresthesia/numbness
5. conjunctivits, excessive lacrimation
38
List the alkylating agents: nitrogen mustards
1. mechlorethamine
2. cyclophosphamide
3. ifosfamide
4. chlorambucil
5. melphalan
39
List the alkylating agents: nitrosureas
1. CCNU (lomustine)
2. BCNU (carmustine)
3. Streptozotocin
40
List the alkylating agents: methylators
1. procarbazine
2. dacarbazine
3. temozolomide
41
Which chemotherapeutic drugs have the following MOA?
1. target DNA via alkylation of DNA base pairs
2. bonding of alkyl groups (-CH2CL) generates highly reactive charged intermediates that react with electron rich nucleophilic groups
alkylators
42
Which of the alkylators require active transport across the cell?
mechlorethamine and melphalan
43
List the drugs that cause alkylation of the O-6 position of guanine.
1. Nitrosureas (CCNU, BCNU, Steptozotocin)
| 2. Meythlating agents (procarbazine, dacarbazine, temozolomide)
44
List the drugs that cause the alkylation of the N-7 position of guanine?
1. Nitrogen mustards (mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, melphalan)
2. Dacarbazine
3. Platinums
45
What is the definition of a mono-functional alkylator?
Contains one reactive group and toxicity caused by ssDNA breaks or damage to DNA base pairs
46
What are the mono-functional alkylators?
1. Nitrosoureas (CCNU, BCNU, Streptozotocin)
| 2. Methylating agents (temozolomide, procarbazine, dacarbazine)
47
What is the definition of a bi-functional alkylator?
1. contains 2 reactive groups and have the ability to form cross-links (inter and intra-strand) btw. DNA strands
2. prevents cell replication unless repaired
3. the most clinically useful
48
What are the bi-functional alkylators?
1. Nitrogen mustards (mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, melphalan)
2. Thiopeta
49
How is damage caused by mono-functional alkylating agents repaired?
1. Repaired by alkylguanine O6-alkyl transferase (AGT) which is encoded by MGMT gene
- Attack O6 methyl group of guanine- can pair with thymine resulting in G:C to A:T during DNA replication
2. MMR
- recognizes mismatch created by alkylation of DNA bases
- repeated attempts to repair O6-meG:T mismatch
- after usuccessful repair, gets ss and ds breaks and cell death
50
What is the mechanism of metabolism and breakdown of cyclophosphamide?
What enzymes causes breakdown of cyclophosphamide?
Hepatic microsomal enzymes metabolize cyclophosphamide to 4-hydroxycylophosphamide, which exists in equilibrium with its acyclic isomer aldophosphamide
4-hydroxycylcophosphamide enters cells and spontaneously decomposes to form phosphoramide mustard and acrolein, or it is inactivated by aldehyde dehydrogenase
Condensed summarized version:
- Is a prodrug and must be broken down:
cyclophosphamide--> 4-OHCOP--> aldophosphamide--> phosphoramide mustard and acrolein
51
Why does ifosfamide cause a different toxicity profile compared to cyclophosphamide?
1. Less affinity for cytochrome p450 enzymes
2. More inactivated by other pathways such as dechlorethylation (why higher doses are needed causing different toxicity profile)
52
Why is ifosfamide renal toxic in cats?
Renal tubules also possess CYP450--> form chloroacetaldehyde--> nephrotoxicity
53
What is the active metabolite of cyclophosphamide?
phosphoramide mustard- the most important for cross-linking activity, bone marrow, and GI toxicity
54
Why is drug exposure to cyclophosphamide after IV significantly higher than oral?
first pass elimination through the liver
55
Why is cyclophosphamide hematopoetic stem cell sparing?
high levels of aldehyde dehydrogenase in HSCs and they convert cyclophosphamide to inactive form
56
What is the dose limiting toxicity for cyclophosphamide and ifosfamide besides myelosuppression? (think, the major one that we always talk about with clients)
sterile hemorrhagic cystitis
| ifosfamide> cyclophosphamide
57
Which drug should be administered to patients receiving ifosfamide in order to prevent SHC?
MESNA (2-mercaptoethane sulfate)
| - conjugates with acrolein
58
Why does ifosfamide cause neurotoxicity?
increased formation of chloroacetylaldehyde
59
Where is the major site of clearance for cyclophosphamide and ifosfamide?
liver
60
What are the mechanisms of resistance of the alkylating agents?
1. decreased transport across cell membrane (mechlorethamine and melphalan require active transport)
2. increased glutathione or glutathione-S-transferase [GST] (free radical scavengers, inactive alkylating agents)
3. decreased detoxification of reactive intermediates (increased aldehyde dehydrogenase)
4. enhanced DNA repair ( increased AGT, MMR deficiency, increased BER/NER/crosslink repair)
5. increased expression of AKT
6. defects in cell cycle arrest/apoptosis
61
What drugs can be administered to decrease resistance of alkylating drugs when there is increased glutathione or GST?
Amifostine, BSO (buthionine sulfoximine)
62
Which drugs decrease resistance to alkylating drugs when AGT repair is high?
O6-benzyl guanine (OBG)
63
Which drugs decrease resistance to alkylating drugs when enhanced DNA repair with BER has occured?
PARP inhibitors
| Methyoxyamine
64
Which drugs decrease resistance to alkylating drugs when there is increased expression of AKT/mTOR pathway?
Rapamycin (inhibits mTOR)
| Wortmannin (inhibits AKT)
65
What are the platinum drugs?
1. Cisplatin
2. Carboplatin
3. Oxaloplatin
4. Satarplatin
66
Which chemotherapy drugs have the following MOA?
covalent binding to DNA through displacement reactions resulting in bifunctional lesions and inter- or intra-strand cross-links
platinums
67
The PK differences in the platinums are due to what?
the differences in the leaving groups
68
What are the differences in the leaving groups for each drug?
1. Cisplatin: 2 chloride leaving groups
2. Carboplatin: substitution of cyclobutanedicarboxylate for the chloride leaving groups
3. Oxaliplatin: substitution of a diaminocyclohexane
69
Describe the crosslinks created by cisplatin and which ones are the most prevelant?
1. covalently binds to 2 sites on DNA (purine= N7 of A or G) = bifunctional adducts
2. 90% of the binding produces intra-strand cross-linkages, usually between 2 adjacent guanine bases or guanine and adenine sites
3. remainder being inter-strand guanine cross-linkages
70
What is considered the critical stereochemistry for the platinum drugs to be clinically active?
cis
Explanation in case you're curious:
1. Platinum drugs can exist in a 2+ (II) or 4+ (IV) oxidation state, with 4 or 6 bonds linking the platinum atom.
2. All currently used platinum drugs are platinum II compounds that exhibit a planar structure and have 4 attached chemical compounds the stereochemistry of the compound is critical (cis)
71
What is the major mechanism by which the leaving groups of the platinums are displaced or moved?
Aquation
Explanation in case you're curious:
1. Have 4 attached chemical compounds
2. Two of the groups are considered carrier groups, and are chemically inert, whereas the 2 leaving groups are available for substitution and reaction with DNA
3. Chlorine atoms (or others) are leaving groups and may be displaced directly by nucleophile groups in DNA or indirectly after chloride ions are replaced by hydroxyl groups through reactions of the drug with water (aquation)
72
Although cisplatin is cell cycle non-specific, which part of the cell cycle does it form cross-links with greatest affinity?
S phase
73
Cisplatin is synergistic with agents that reduce intracellular levels of purine and pyrimidine precursors needed for DNA replication and repair. What are 2 examples?
5-FU
| Gemcitabine
74
Why is oxaliplatin synergistic with the antimetabolites?
down-regulates thymidylate synthase
75
For platinums, their effect in killing of tumor cells or toxicity to normal tissues is related to what? Choose one
AUC
Peak drug level
AUC
76
The excretion or clearance of carboplatin is highly dependent on what two things?
GFR and renal clearance
77
What is the expected neutrophil and platelet nadir of carboplatin?
Double nadir: common at day 14 and day 21
78
What is most unique about Satraplatin in dogs regarding the following:
1. stability?
2. route of admin?
3. toxicity?
4. metabolite with anticancer activity?
5. adducts?
6. nadir?
1. more lipophilic and stable than other agents
2. allows PO admin and bioavailability
3. less neuro/nephrotoxic
4. JM118
5. creates bulky adducts in DNA- more difficult for repair
6. plt nadir before neut nadir (14 vs 19 days)
79
What does a higher AUC after the 5th dose vs the 1st dose of satraplatin suggest?
drug accumulation in tissues b/c its more lipophilic (detectable 2 weeks after cessation of therapy)
80
The platinums enter and exit the cells via which process?
diffusion
| active transporters
81
What are the mechanisms of resistance of the platinums?
1. altered cellular accumulation (increased efflux)
2. cytosolic inactivation of drug (glutathione)
3. altered DNA repair (increased NER- repairs bulky adducts)
4. resistance to apoptosis (decreased MMR, defective MMR proteins)
82
What occurs with renal toxicity from cispatin:
1. what cations are wasted?
2. which tubules?
3. blood work changes?
1. Cation wasting (Mg, Ca)
2. distal more affected than proximal
3. creatinine may not be good indicator of reduced renal fxn- can be normal
83
What is the most severe side effect of cisplatin in cats?
fatal pulmonary edema
84
Which of the platinums causes neurotoxicity and ototoxicity?
cisplatin
85
Which chemotherapeutic has the following MoA?
1. Cellular uptake depends on GLUT2 transporter expression
2. Unique methylnitrosurea with methylating activity that lacks carbamoylating activity
Streptozotocin
86
Which chemotherapeutic has the following MoA?
1. Methylator that acts at N7 guanine, O3 adenine and O6 guanine (in decreasing frequency)
2. Prodrug that requires activation
Temozolomide
•Side note: causes fatal pleural and pericardial effusion in cats
