Fitzy 3 and 4: Antimitotic and G/M phase drugs Flashcards
1
Q
What are the 2 classes of antimitotic drugs?
A
vina alkaloids
taxanes
2
Q
3 members of vinca alkaloid family?
A
Vinblastine
Vincristine
Vinorelbine
3
Q
2 members of the Taxanes family
A
Taxol and Taxotere
4
Q
What do the Vinca alkaloids do?
A
inhibit tubulin polymerization
-block assembly of microtubules
5
Q
What do the taxanes do?
A
Enhance tubulin polymerization
-stabilize microtubules
6
Q
Therepeutic (TU) use of Vinblastine?
A
Testicular cancer, lymphomas, neuroblastoma
7
Q
TU of Vincristine?
A
ALL, lymphoma, neuroblastoma, Wilms tumor, Ewings sarcoma
8
Q
TU of vinorelbine
A
Advanced NSCL cancer
9
Q
TU of Paclitaxel?
A
advanced breast and ovarian
10
Q
Docetaxel
A
Advanced breast, ovarian recurrence
11
Q
What are taxanes effective against?
A
solid tumors (this was in bold red soo watch out
12
Q
Vinblastine toxicity
A
Bone marrow suppression; vesicant-blisters
13
Q
Vincristine toxicity
A
NEurotoxitcity; peripheral neuropathy (these two bolded in red
-paralytic ileus; vesicant-blisters
14
Q
Vinorelbine toxicity
A
Bone marrow suppression; vesicant-blisters
15
Q
Paclitaxel toxicity
A
neutropenia; Thrombocytopenia; peripheral neuropathy; sever hypersensitivity during infusion- requires anti-histamine and coricosteroid pretreatment
16
Q
Docetaxel toxicity
A
Neutropenia; peripheral neuropathy`
17
Q
Antimitotic drugs MOA?
A
disruption of microtubule stability
18
Q
Vinca Alkaloids MOA?
A
inhibit tubulin polymerization
- they just stop what’s happening at the positive forming end of the microtubule
- meanwhile, the negative end keeps fraying off
19
Q
MOA of Taxanes?
A
bind to Btubulin at the forming end of microtubules…
- the taxane-tubulin complexes migrate to the negative end… inhibit depolymerization
- they stop the negative end from fraying off
- enhances tubulin polymerization and stabilizes microtubules
20
Q
So, since Vinca alkaloids and taxane drugs impair spindle integrity, what phase of the cell cycle do they act at?
A
the M phase!
21
Q
What were the S phase antimetabolites again?
A
5FU Capecitabine AraC Gemcitabine MTX and pemetrexed Thiopurines- 6MP, 6TG Cladribine, fludarabine
22
Q
What are the M-Phase antimitotics again?
A
Taxanes: Paclitaxel and docetaxel
Vinca alkaloids: vinblastine, vincristine, vinorelbine
23
Q
What do we replace vincristine with when it starts giving us neuropathy?
A
Vinblastine
24
Q
What does treatment with these drugs lead to ?
A
Multi drug resistance
25
Why does MDR occur here?
due to incrased expression of P-glycoprotein and its enhanced extrusion of drugs from the tumor cell
26
How are the Vinca Alkaloids and taxanes administered?
IV
- metabolized by liver,
- so, impaired hepatic function warrants dose adjustment
27
What happens with ppl being treated for metastatic cancer 90% of the time when we use these drugs?
MDR :(
28
What does the p glycoprotein do exactly?
pumpes the drugs out of the cell
| -efflux pump
29
What drugs are not prone to P-glycoprotein drug resistance?
drugs that work outside the cell
| -monoclonal antibodies
30
What are the drugs that cause DNA strand breaks?
Topoisomerase inhibitors
31
What are the 2 classes of Topoisomerase inhibitors
Epipodophyllotoxins
| camptothecins
32
Epipodophyllotoxins class members?
Etoposide and teniposide
33
Camptothecins class members?
Irinotecan and topotecan
34
Active metabolite of irinotecan?
SN38
35
What do the epipodophyllotoxins do?
Inhibit topoisomerase 2
| -leads to DOUBLE strand breaks which is nice
36
What do the camptothecins do?
Inhibit topoisomerase 1
| -causes DNA single strand breaks
37
TU of etoposide?
OAT cell carcinoma of lung; testicular cancer
38
TU of teniposide
glioma and neuroblastoma
39
TU of irinotecan
Metastatic colorectal cancer
40
TU of topotecan
2nd line various-failed prior 1st line (bolded in red)....
41
Etoposide toxicity?
leukopenia; secondary cancer
42
Teniposide toxicity?
leukopenia
43
Irinotecan toxicity
Severe diarrhea; myelosuppression
44
Topotecan toxicit
neutropenia; mucositis
45
How are these topoisomerase inhibitors administered?
IV
46
How is Etoposide and teniposide cleared?
CYP450 in liver
47
how is irinotecan and topotecan cleared?
Renal clearance
48
MOA of topoisomerase inhibitors?
Bind to DNA-enyme complex and created a persistently cleavable complex
49
What phase of cell cycle do the TI 1 inhibitors work at?
S phase
50
Cell cycle phase for TI 2 inhibitors?
mixed?
51
What are the 2 classes of drugs that cause DNA strand breaks by intercalation of oxidative scission?
Antibiotics
| Anthracyclines
52
Antibiotics?
- Bleomycin (bolded)
| - Dactinomycin
53
Anthracyclines?
```
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Mistoxantrone
```
54
What does bleomycin do?
Fe mediated free radical generation
| -dna strand breaks
55
What does dactinomycin do?
DNA intercalation
56
What does Doxo, dauno, epi, and idarubicin do?
- inhibit TI2
- DNA intrecalating
- Free radical generation
- DNA strand breaks
57
What does Mitoxantrone do?
inhibit TI2
58
TU of Bleomycin
testicular cancer
59
TU of doxorubicin and epirubicin
wide spectrum-breast, ovarian, lung, thyroid, lymphoma, sarcoma
60
TU of daunorubicin
Leukemia (AML, ALL)
61
TU of Idarubicin
Leukemia (AML, ALL, CML in blast crisis)
62
TU of MItoxantrone?
breast, prostate, non-hodgkin lymphoma
63
Bleomycin toxicity (you better fucking get this one right)
Pulmonary fibrosis!!!!*****
64
The "rubicin" toxicity
Cardiotoxicity, dilated cardiomyopathy, congestiv heart failure
65
Mitoxantrone toxicity
Similar to rubicins
66
Doxorubicin MOA?
intercalating agent
-it's really flat, inserts into DNA... creates distortions
-inhihbits RNA synth and replication as well
it also make superoxides out of O2
67
What does Bleomycin cause damage to?
skin and lung because those tissues do not have the enzyme required to metabolize bleomycin
68
What bleomycin cause siginificant myelosuppression?
NO!
69
What element does bleomycin use to make radicals?
Fe
70
What does Bleomycin give us again as a nasty side effect?
fibrosis
71
What toxicity does doxorubicin give us again?
dilated cardiomyopathy
72
What phase of the cell cycle do the anthracyclines (doxorubicin) and bleomycin act?
G2 phase
73
What do we want to keep in mind when choosing a chemotherapy regimen?
use drug combos that distribute toxicity among different organs
74
What is the ABVD regimen for Hodgkin lymphoma?
Adriamycin (doxorubicin)
Bleomycin
Vinblastine
Dacarbazine
75
What is the toxicities with each of the ABVD drugs?
Adriamycin (doxorubicin): dilated cardiomyopathy
Bleomycin: pulmonary fibrosis
Vinblastine: peripheral neuropathy
Dacarbazine: Nausea/vomiting and myelosuppression
76
Activity, clearance, and toxicity of Doxorubicin (A)
- DNA damage and intercalating agent
- Hepatic metabolism
- cardiomyopathy
77
Activity, clearance, and toxicity of Bleomycin (B)
- anti tumor antibiotic
- renal
- pulmonary fibrosis
78
Activity, clearance, and toxicity of Vinblastine (V)
- Antimitotic, destabilizes microtubules
- CYP3A4/5 metabolism
- Neuropathy
79
Activity, clearance, and toxicity of Dacarbazine (D)
- DNA damage alkylating agent
- Hepatic metabolism
- Marrow suppression
80
What is the CHOP regimen used for?
Non-hodgkin lymphoma
81
What is the CHOP regimen?
- Cyclophosphamide
- Hydroxydaunorubicin (Doxorubicin)
- Oncovin (Vincristine)
- Prednisone
82
What are the toxicities of the CHOP regimen?
Cyclophosphamide: hemorrhagic cystitis
Hydroxydaunorubicin: cardiotoxicity
Oncovin: peripheral neuropathy
Prednisone: Hyperglycemia, osteopenia
83
Activity, clearance, and toxicity of Cyclophosphamide?
- alkylating agent
- CYP3A4/5 CYP2D6 pro-drug
- Acrolein.... leads to hemorrhagic cysts
84
Activity, clearance, and toxicity of Doxorubicin (H)
- DNA damage, intercalating agent
- Hepatic metabolism
- Cardiomyopathy
85
Activity, clearance, and toxicity of Vincristine (O)
- Anti-mitotic, destabilizes microtubules
- CYP3A4/5
- NEuropathy, constipation
86
Activity, clearance, and toxicity of prednisone (P)
- corticosteroid
- 100% bioavailable
- Hyperglycemia, osteopenia
87
What does allopurinol and febuxostat do?
inhibit Xanthine oxidase
- this way, Uric acid can't be made and won't build up
- this is a treatment for gout
88
What's wrong with inhibiting XO?
XO metabolizes drugs use din cancer chemotherapy
| -confers risk of overexposure and requirs dose adjustments
89
What drugs are metabolized by XO tha will build up?
- 6Mercaptopurine
- Azathioprine
- theophylline
90
What happens when we kill a shit ton of cells using chemotherapy?
those cells release their contents into our body
| -hyperuricemia, electrolyte complications
91
How is acute nephrotoxicity produced by excessive uric acid managed?
administration of allopurinol, and xanthine oxidase inhibitor
92
Where does all that uric acid come from anyways?
break down of purines from dead cells
93
What all gets released when cells get killed like that?
- K+
- Phosphate: leads to hypocalcemia
- Uric acid
94
If we give a patient Allopurinol and 6-mercaptopurine, what will happen?
can result in excessive exposure to 6-MP because that is metabolized by XO which is being inhibited by Allopurinol
-just reduce the dose of 6-MP
95
What does Pegloticase do?
turns uric acid into Allantoin
96
What does chemotherapy make people do a lot?
throw up: nausea and vomiting
97
How does chemotherapy induce nausea and vomiting?
- direct activation of medullary CTZ
| - Cell damage of the GI tract: 5HT3 receptors get activated on enterochromaffin cells
98
What will we do to help with the nausea and vomiting?
give them a setron... 5-HT3 receptor antagonist
