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Combined Treatments Flashcards

1
Q

How does irinotecan (Camptosar) work?

A
  • Topoisomerase I inhibitor
  • Synthetic analog of camptothecin (CPT), a natural product from the bark and stem of the Camptotheca plant
  • It stabilizes topoisomerase-DNA cleavable complex after cutting DNA
  • This blocks DNA from being re-ligated
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2
Q

How does cetuximab (Erbitux) work?

A
  • Monoclonal Ab against EGFR
  • Inhibits EGFR dimerization
  • Strong synergy with radiation
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3
Q

How does bevacizumab (Avastin) work?

A
  • Humanized monoclonal Ab against VEGF ligand, not VEGF receptor
  • Blocks VEGF-A (angiogenesis)
  • Tumor stroma-directed therapy!
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4
Q

How does Bortezomib (Velcade) work?

A
  • N-protected dipeptide
  • It is a 26S proteasome inhibitor
  • By blocking it, it prevents the degradation of pro-apoptotic factors → apoptosis
  • Approved for multiple myeloma and mantle cell lymphoma

Mnemonic: Bortezomib → bore (proteasome)

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5
Q

How does Sirolimus (Rapamycin) work?

A
  • It is an immunosuppressant
  • Binds to FK-binding protein 12 (FKBP12)
  • Inhibits the target of Rapamycin (mTOR pathway)

Mnemonic: Sirlimus fucks (FKBP12)

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6
Q

How does Rapamycin work?

A

mTOR/FRAP inhibitor

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7
Q

When do we use FLT-3 inhibitors and why?

A
  • Activating mutations in FMS-like tyrosine kinase 3 (FLT3) → 30% pts with AML
  • FLT3 inhibitors (usually TKIs) block FLT3 activity
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8
Q

What are some examples of nitrogen mustards and how do they work?

A
  • Cyclophosphamide, ifosfamide, etc
  • Crosslink DNA → DNA replication & transcription inhibited → cell cycle arrest, apoptosis
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9
Q

What is the role of Cyclooxygenase (COX-2) inhibitors?

A

They block the COX-2 enzyme, which is produced in response to inflammation, and by precancerous and cancerous cells.

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10
Q

What is the role of COX-2?

A
  • Mediate synthesis of eicosanoids (like prostaglandins) from arachidonic acid
  • COX-2 products are inflammatory
  • It is over-expressed in tumors
  • It is normally not produced in healthy tissues
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11
Q

How does erlotinib (Tarceva) work?

A
  • Small-molecule EGFR TKI
  • Reversibly binds to the ATP binding site of the receptor
  • Prevents downstream signaling
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12
Q

How does gemcitabine work?

A
  • It is an anti-metabolite, analog of deoxycytidine
    — Is incorporated into DNA, inhibiting further DNA synthesis
  • Inhibits ribonucleotide reductase (radiosensitization), causing depletion of deoxynucleotide triphosphates necessary for DNA synthesis

Mnemonic: Used for pancreatic cancer (pancreas is a major player in metabolism)

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13
Q

How does etoposide work?

A

Poisons Topoisomerase II

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14
Q

Which cellular feature is responsible for resistance to melphalan?

A

Presence of Glutathione

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15
Q

How does melphalan work?

A

Alkylating agent

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16
Q

How does methotrexate work?

A
  • Anti-metabolite
  • Competitive inhibitor of dihydrofolate reductase
  • Decreased cellular reduced folate levels
  • Decreased synthesis of purines (A,G)
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17
Q

How does chlorambucil work?

A
  • DNA alkylation
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18
Q

How does imatinib (Gleevec) work?

A
  • It’s a TKI
  • Blocks the ATP-binding site of the p210 tyrosine kinase domain of the BCR-ABL fusion protein in CML
  • Most specific for BCR-ABL, but has activity against c-kit, and PDGF-R as well
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19
Q

How does doxorubicin (adriamycin) work?

A
  • Anthracycline
  • MOA1: Blocks Topoisomerase II
  • MOA2: Intercalates within DNA
  • Inhibits both DNA and RNA synthesis
  • Notorious for its cardiotoxicity

doxorubicin → dual actions (RNA/DNA, MOA1/2)

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20
Q

What’s the MOA of Vincristine and Vinblastine?

A
  • Binds tubulin dimers
  • Inhibits microtubule assembly
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21
Q

What’s the MOA of cisplatin?

A
  • Alkylates DNA (similar to alkylating agents)
  • Forms inter- and intra-strand DNA strand crosslinks
  • Cell cycle non-specific
  • Inhibits DNA synthesis
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22
Q

What is the MOA of enzalutamide (Xtandi)?

A

Androgen receptor antagonist

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23
Q

What’s the MOA of abiraterone (Zytiga)?

A
  • Inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1)
  • It is an enzyme expressed in testicular, adrenal, and prostatic tumor tissues
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24
Q

What’s the MOA of Leuprolide (Eligard)?

A

It’s an Luteinizing hormone-releasing hormone (LHRH) agonist

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25
What's the MOA of denosumab (Xgeva, Prolia)?
- Inhibits the ligand (RANKL) for osteoprotegerin - Inhibits osteoclast differentiation and activation
26
How does Ra-223 work?
- It is a bone-seeking (similar to calcium) - 95% α -particle emitter (5% β & γ) - α-particles have short range, delivering high doses of radiation to osteogenic cells and very low doses to surrounding healthy tissue
27
What's the MOA of Ipilimumab (Yervoy)?
It binds to CTLA-4
28
What's the mnemonic for immune checkpoint inhibitors and their targets?
- NP, ADd IT -- PD-1: Nivolumab, Pembrolizumab -- PD-L1: Atezolizumab, durvalumab -- CTLA-4: Ipilimumab, Tremelimumab
29
What's the MOA of crizotinib (Xalkori)?
- Small molecule TKI (**tinib**) - Inhibits ALK and ROS1 kinases - Targets the ALK-EML4 fusion gene, and ROS-1 mutated cancers - Used for NSCLCs, 5% of which have EML4-ALK translocations
30
What's the incidence of cisplatin-induced acute kidney injury (AKI)?
- AKI in 20-30% of patients within 3-5 days - More common w/ cisplatin delivered q3 weeks at 100 mg/m2 compared to weekly at 40 mg/m2
31
How does cisplatin cause AKI?
- Kidney injury is related to mitochondrial density and membrane potential - Proximal tubules have the highest density and are most sensitive to cisplatin - It can also form superoxide anions in the glomerulus and proximal tubules, but NOT distal tubules Mnemonic: Cis**p**latin damages **p**roximal tubules
32
Which lab abnormality correlates with AKI?
Serum Cr > 1.5 x baseline
33
How does treatment with an anti-angiogenic agent increase tumor sensitivity to radiation?
There is a **transient normalization of tumor vasculature**, which results in increased perfusion and increased O2 delivery, leading to a decrease in hypoxia-induced radioresistance.
34
Has misonidazole shown any benefit when given together with radiation?
- **No** - Multiple RTOG trials using misonidazole have failed to show a benefit. - **Only Nimorazole** has demonstrated a benefit in a single DAHANCA trial
35
Why is nimorazole used instead of other drugs (misonidazole, etanidazole, etc) in its class?
- It has acceptable toxicity (peripheral neuropathy) - But it is less effective than the other drugs
36
How do the nitroimidazoles work?
They have a NO2 group, which has a longer diffusion distance than O2 and can lead to hypoxic radiosensitization.
37
What was the effect of hypoxic cell radiosensitizers on LRC and OS according to the Overgaard meta-analysis?
They increased both LRC and OS compared to RT alone.
38
Why can radiosensitizers be advantageous for SBRT?
Reoxygenation does not occur as readily during SBRT. Thus, hypoxic cell radiosensitizers can be especially helpful.
39
Where inside a tumor do cancer stem cells reside?
Hypoxic regions
40
What is the MOA of radiation protector/mitigator flagellin?
- **F**lagelli**n** activates **NF**-kB - NF-kB upregulates anti-apoptotic genes -- Cytokines and growth factors -- Antioxidant scavengers (MnSOD)
41
How does Hsp90 inhibition → Radiosensitization?
- Tumor cells exist in very stressful environments, which include acute and chronic hypoxia, increased levels of DNA damage, high levels of ROS, and protein complex imbalances. - Their survival is aided by efficient cellular stress response machinery, such as heat shock protein (Hsp90). - Inhibition of Hsp90 can make a tumor more radiosensitive.
42
How does nelfinavir, an HIV protease inhibitor, cause radiosensitization?
- Enhances the effect of ionizing radiation on endothelial cells - Downregulates VEGF expression in tumor cells via hypoxia-inducible factor 1α - Inhibits PI3K-AKT-mTOR pathway - Activates the unfolded protein response
43
How does ADT act in concert with radiation?
It represses an androgen receptor gene expression program governing DNA repair and inhibits the repair of ionizing radiation-induced DNA damage
44
How does Palifermin decrease mucositis after radiation?
Palifermin is a human recombinant keratinocyte growth factor that stimulates the proliferation of GI tract mucosal cells, decreasing the severity of side effects. Mnemonic: Pali**firm**in → firms up mucosa using keratin
45
What is a small molecule drug?
A drug that can enter cells easily because it has a low molecular weight. Once inside the cells, it can affect other molecules, such as proteins, and may cause cancer cells to die. This is different from drugs that have a large molecular weight, which keeps them from getting inside cells easily. Many targeted therapies are small-molecule drugs.
46
How do proteasomes work?
They break down proteins targeted for elimination (ubiquitination).
47
How does capecitabine (Xeloda) work?
- It's a prodrug of 5-FU taken orally
48
How does 5-FU work?
- Anti-metabolite - Inhibits thymidylate synthase - Impairs DNA, rRNA, and mRNA synthesis
49
How does Sorafenib work?
- Small molecule, a "dirty" multi-kinase inhibitor - Approved for use in patients with advanced renal cell carcinoma, hepatocellular carcinoma, and RI-resistant thyroid carcinoma
50
How does nivolumab (Opdivo) work?
- Human IgG4 monoclonal antibody - Binds to programmed death (PD-1) receptor, preventing it from binding to PD-L1 and 2.
51
How does Rituximab work?
- Ab against CD20 - Used for CD20-positive lymphomas → apoptosis and cell lysis
52
How does Gefitinib work?
- Small molecule EGFR TKI - Approved for EGFR exon 19 deleted or EGFR exon 21 mutated non-small cell lung cancer (NSCLC).
53
How does Misonidazaole work?
It is a hypoxic radiosensitizer
54
How does Tirapazamine work?
- Bioreductive drug -- bioreduced to a toxic radical in hypoxic cells -- technically **not** a hypoxic cell radiosensitizer - Standard Research # (SR4233)
55
How does topoisomerase I work?
It catalyzes transient breaking and rejoining of single-strand DNA, which lets the broken strand rotate around the intact strand.
56
How does topoisomerase II work?
It cuts both DNA strands to manage DNA tangles and supercoils
57
What are some topoisomerase I inhibitors?
- Irinotecan - Topotecan
58
What are some topoisomerase II inhibitors?
- Etoposide - Doxorubicin - Daunorubicin - **Mitoxantrone**
59
How does Sunitinib work?
- **Dirty** multi-target receptor kinase inhibitor -- Targets include EGFR, FLT3, VEGFR, and KIT - Approved for gastrointestinal stromal cells (GIST) and renal cell carcinomas
60
How can multi-drug resistance (MDR) 2/2 membrane transporter be reversed?
With Verapamil, a Ca2+ channel blocker
61
How does multi-drug resistance (MDR) normally develop?
- Usually 2/2 MDR gene - Can be caused by either an increase in **p100-glycoprotein** or other proteins that increase drug efflux non-specifically - Can also be caused by amplification of DNA repair genes
62
Which drugs are people w/ fanconi anemia most hypersensitive to?
- They cannot repair DNA interstrand crosslinks, so are most sensitive to: -- Platinum agents -- Cyclophosphamide
63
How is the efficacy of mitomycin C related to aeration?
- Bioreductive drug - Crosslinks DNA - More toxic under hypoxic conditions
64
What is photodynamic therapy (PDT)?
- Uses drugs activated by **visible light** (600-900 nm) - Forms **singlet oxygen radicals** (NOT hydroxyl); highly toxic - Effective in **oxic tissues** — Ineffective in hypoxic tissues - Can be used for superficial tumors - Can also be used for deep tumors that can be accessed via fiberoptic probes - **Hematoporphyrin and its derivatives** are the most common clinically used photodynamic therapeutics
65
How does the efficacy of cisplatin compare to its isomer, trans-platinum?
It is more effective than its isomer.
66
What's the toxicity most a/w bleomycin?
Pulmonary toxicity
67
Which drug is a/w an increased survival when patients develop a grade 2 or higher acneiform rash?
Cetuximab!
68
How does Ipilimumab work?
- Small molecule inhibitor - Targets CTLA-4
69
What does ALK stand for?
Anaplastic lymphoma kinase
70
What is synthetic lethality?
It is a concept whereby a defect in one of a pair of genes does not affect survival, but a defect in both results in cell death. Eg: PARP and BRCA 1/2 genes
71
What's the MOA of Panitumumab (Vectibix)?
- Humanized IgG2 Ab against EGFR
72
What's the MOA of Infliximab?
- Monoclonal Ab against TNF-α (I**nf**lixim**α** b) - Used for rheumatoid arthritis and psoriasis
73
How is Y-90 used in the tx of lymphomas?
Bound to an anti-CD20 Ab (Ibritumomab tiuxetan)
74
What is adaptive immune resistance?
It's the process by which tumor cells change phenotype in response to an immune response (cytotoxicity or inflammation) in an attempt to avoid recognition
75
What risk factors put patients at an increased risk for experiencing an immune-related adverse event?
- Autoimmune disease hx - Prior checkpoint blockage therapy - Prior radiation therapy
76
What is the dose-limiting toxicity of hypoxic radiosensitizers ("imidazoles") that has led to disappointing clinical trial results?
Peripheral neuropathy
77
What are bioreductive drugs?
- Metabolically reduced to yield cytotoxic species - Happens under hypoxic conditions - Do not need radiation for effect
78
At what doses and radiation fx sizes are hypoxic cell radiosensitizers most effective?
- High doses - Large fx sizes (hypofractionation, SBRT)
79
Is Amifostine a pro-drug? How does it work?
- Pro-drug hydrolyzed to the active form (a free thiol compound) by alkaline phosphatase (**fos**phatase) - Must be given IV for maximum efficacy
80
What are the main side effects of amifostine?
- Fatigue - Fever - Rash - Hypotension - Nausea/vomiting
81
Does Cisplatin form more interstrand or intrastrand crosslinks?
Intra
82
What pathway is responsible for Cisplatin's radiosensitization effect?
Inhibition of DNA double-strand break repair
83
Under what conditions is temozolomide most effective?
When there is epigenetic silencing of the MGMT gene through hypermethylation
84
How does methylation affect the MGMT gene?
Silences it
85
How does methylation of the MGMT gene increase the efficacy of radiation & temozolomide?
- Temozolomide creates DNA alkylation, which cannot be repaired by MGMT 2/2 hypermethylation.
86
What's the function of Wee1 and how does it control radiosensitization?
- Wee1 controls the G2/M checkpoint - This checkpoint is important after RT for DNA damage repair - Wee1 inhibition, through MK1775, causes cells to go into mitosis w/ damaged DNA → mitotic catastrophe
87
What's the fx of LAG3?
- It is an immune checkpoint inhibitor, much like PD-1 and CTLA-4 - It's main ligand is MHC class II
88
What's the MOA of alectinib?
- TKI - Used for ALK (**AL**e**K**tinib)-fusion +ve NSCLC - Efficacy demonstrated in J-ALEX and ALEX trials - Less toxic than Crizotinib - Crosses BBB and can delay CNS brain met the progression
89
What tumor feature is a/w response to immune checkpoint blockade?
- Somatic mutation load - The more mutation a tumor has → the higher the chance that it will respond well to immune checkpoint blockade
90
What's the MOA of superoxide dismutase?
- SOD contains a redox-active metal ion that is oxidized in the presence of superoxide (O2-) - Mechanism of action involves converting superoxide (O2-) into hydrogen peroxide (H2O2) - Can protect against RT- and chemotherapy-induced oral mucositis
91
What are some other names for Amifostine?
Ethyol WR 2721
92
What side effect is amifostine FDA-approved to protect against?
H&N cancer treatment-related xerostomia
93
What side effect is amifostine FDA-approved to protect against?
H&N cancer treatment-related xerostomia
94
How does Ibritumomab work?
- Radiotherapeutic - B-cell CD-20 antibody -- Mnemonic: **ritu** like rituximab - Radiolabelled w/ Y-90
95
How do small molecule tyrosine kinases (TKIs) work?
- ATP-mimetics - Bind to the ATP-binding domain of receptor TKs - Activity against multiple tyrosine kinases (as opposed to antibodies, which are highly specific) - Can inhibit both stromal and cancer cell TKs, in a ligand-independent manner - All TKIs, not just small molecule TKIs, can be given with radiation and chemotherapy
96
If a drug has tinib in its name, what does it mean?
- It is a small molecule TKI (antibody TKIs will have mabs at the end of their names)
97
How are all TKIs administered?
Orally
98
What's the MOA of bleomycin?
- Produces free radicals → single and double-strand DNA break - "Radiomimetic"
99
Why is bleomycin most effective in oxic tissues?
Because metals and O2 are required for Bleomycin to cause DNA damage.
100
What is the MOA of dactinomycin?
- Inhibitor of RNA synthesis - Strong synergy with radiation
101
What's the MOA of Ara-C?
- Converted to its active form, ara-CTP - Competitive DNA polymerase inhibitor -- Menmonic: Ara-**C** (C is one of the bases in DNA)
102
What's the MOA of vorinostat (suberoylanilide hydroxamic acid (SAHA)), valproic acid, and MS-275?
- It is a histone deacetylase inhibitor (HDACI) - Enhances acetylation - Acetylation relaxes DNA, making it more accessible to the transcription machinery - HDACIs can cause growth arrest, apoptosis, autophagy, mitotic catastrophe, senescence, anti-angiogenesis, and cell death.
103
What is the MOA of PARP inhibitors?
- Impair base excision repair (BER) specific for single-strand breaks - Cause dsDNA breaks, which require HR to repair - Toxic in tumors with BRCA1/2 mutations - Important within the context of synthetic lethality
104
What are halogenated pyrimidines?
- They have a halogen in place of a methyl group (I-dUdR, Br-dUdR - Incorporated into the DNA in place of T - DNA is weakened, making it more susceptible to damage by UV light or radiation - Need to be given for several generations for efficient DNA integration - Not used clinically as much
105
What does Br-dUdR sensitize the cells that I-dUdR does not?
- Fluorescent light - Pts get a skin rash
106
What are hypoxic radiosensitizers?
- Oxygen substitutes that diffuse into poorly vascularized areas of the tumor - Reach all hypoxic cells (diffuse further than O2) - Not rapidly metabolized by cells - Highly soluble in water and lipids
107
What is suicide gene therapy?
- A gene for an enzyme is inserted into the tumor cells via a viral vector. - A non-toxic prodrug is administered - This prodrug is converted into the active toxic drug by the enzyme → cell killing
108
How does hydroxyurea work?
It inhibits ribonucleotide reductase → DNA synthesis inhibition
109
What are Farnesyl transferase inhibitors (FTI)?
- Inhibit the fx RAS - RAS requires farnesylation to function
110
What's the MOA of taxanes?
- Promote microtubule assembly (stabilize them) - Prolong G2/M phase - Synergize with radiation
111
How does Cytarabine work?
- A nucleoside analog that blocks DNA synthesis - Specific to the S phase
112
What tumor feature is predictive of a good response to PD-1/PD-L1 inhibitors?
- Tumor infiltration by CD9+ T-cells! - High levels of cancer cell PD-L1 expression - High cancer genome mutational burden
113
What's pleiotropic chemoresistance?
- When resistance to one chemotherapy drug results in cross-resistance to other drugs - Usually occurs in cancer cells w/ the MDR gene/protein product
114
What were the results of the accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) trial?
- Carbogen and nicotinamide are two agents thought to overcome hypoxia -- Nicotinamide overcomes acute hypoxia by preventing transient changes in blood flow -- Carbogen (95% O2, 5% CO2) overcomes chronic hypoxia by increasing passive O2 diffusion into tissues - ARCON showed: -- Similar rates of local control (78% vs. 79%) --- Failed primary endpoint -- Improved regional control (93% vs. 97%) -- Similar toxicity
115
What's the target and MOA of Vemurafenib?
- Targets B-Raf V600E mutation - Commonly used for melanomas
116
What's the target and MOA of Osimertinib?
- Small molecule TKI against EGFR - Targets T790M mutation -- Frequently acquired after exposure to erlotinib and gefitinib
117
Which newer class of medications are a/w significant risk of immune side effects?
- PD1/PD-L1 inhibitors
118
What's I-131 used for?
- I-131: Radionuclide used to tx thyroid ca and hyperthyroidism - Dose: -- Thyroid Ca s/p resection: 0.5-1 Gy
119
Dose-survival cure for most chemotherapies follows what order kinetics?
- First-order kinetics -- A given dose kills a constant fx of cells, regardless of the population size - On a log scale, this looks very much like that of ionizing radiation - There are exceptions to this, such as adriamycin and bleomycin
120
Which chemotherapeutic/systemic txs have better BBB penetration?
- Nucleoside analogues - alkylating agents - antimetabolites
121
Which chemotherapeutic/systemic txs have poorer BBB penetration?
- Antibiotics (-mycins) - Taxanes - Topoisomerase inhibitors
122
Which taxane can cross the BBB, which the general drug class normally cannot do?
- Ca**b**azitaxel -- Mnemonic: B for the brain
123
Which drug inhibits CDK4/6?
Palbociclib -- Mnemonic: "cyclib" → inhibits cell cycle
124
What's the MOA of Relatimab?
- Targets LAG-3 (re**lag**timab) - Expressed in activated T cells, LAG-3 prevents excess T cell activation. -- Inhibiting LAG-3 leads to increased T cell activation
125
Combination of a targeted agent against which proteins and radiation give elevated GI toxicity?
VEGF/VEGFR

RadBio (10 decks)

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