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Heme/Lymph - Exam 1 > Intro to Antineoplastic Agents - SRS > Flashcards

Intro to Antineoplastic Agents - SRS Flashcards

1
Q

What are the three super categories of classic antineoplastic drugs?

A
  1. Alkylating Agents
  2. Natural Products
  3. Antimetabolites
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2
Q

What are the 6 subcategories of alkylating agents?

A
  1. Nitrogen Mustards
  2. Methylhydrazine derivative
  3. Alkyl sulfonate
  4. Nitrosoureas
  5. Triazenes
  6. Platinum Coordination complexes
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3
Q

What are the 6 sub categories of natural product antineoplastics?

A
  1. Vinca alkaloids
  2. Taxanes
  3. Epipodophyllotoxins
  4. Camptothecins
  5. Antibiotics
  6. Enzymes
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4
Q

What are the three subcategories of antimetabolite antineoplastic drugs?

A
  1. Folic acid analogues
  2. pyrimidine analogs
  3. purine analogs
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5
Q

What are the nitrogen mustard antineoplastics on our drug list?

5 with 2 BOLD

A
  1. •Chlorambucil
  2. •Cyclophosphamide
  3. •Ifosfamide
  4. •Mechlorethamine
  5. •Melphalan
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6
Q

What is the one (non-nbold) methlhydrazine derivative on the drug list?

A

Procarbazine

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7
Q

What is the alkyl sulfonate antineoplastic drug that is on our drug list?

1 BOLD

A

Busulfan

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8
Q

What are the three nitrosoureas on our drug list?

None bold

A
  1. •Bendamustine
  2. •Carmustine
  3. •Streptozocin
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9
Q

What are the two (non-bold) triazenes?

A
  1. •Dacarbazine
  2. •Temozolomide
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10
Q

What are the three platinum coordination complexes on our drug list?

(ONE BOLD)

A
  1. •Carboplatin
  2. •Cisplatin
  3. •Oxaliplatin
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11
Q

What are the three vinca alkaloids on the drug list? (2 bold)

A
  1. •Vinblastine
  2. •Vincristine
  3. •Vinorelbine
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12
Q

What are the two taxanes? (one bold)

A
  1. •Docetaxel
  2. •Paclitaxel
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13
Q

What are the two Epipodophyllotoxins on our drug list?

A
  1. •Etoposide
  2. •Teniposide
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14
Q

What are the two camptothecins on our list? (no bold)

A
  1. •Irinotecan
  2. •Topotecan
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15
Q

What are the seven antibiotics for neoplasms on our drug list?

(Two BOLD)

A
  1. •Bleomycin
  2. •Dactinomycin (actinomycin D)
  3. •Daunorubicin
  4. •Doxorubicin
  5. •Mitomycin C
  6. •Mitoxantrone
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16
Q

What are the two enzyme drugs on our list? (one bold)

A
  1. •L-Asparaginase
  2. •Pegaspargase
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17
Q

What are the two folic acid analogs? (one bold)

A
  1. Methotrexate (MTX)
  2. Pemetrexed
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18
Q

What are the 6 pyrimidine analogs on our list? (one BOLD)

A
  1. 5-aza-cytidine
  2. Capecitabine
  3. Cytarabine (cytosine arabinoside)
  4. Deoxy-5-aza-cytidine
  5. Fluorouracil (5-fluorouracil; 5-FU)
  6. Gemcitabine
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19
Q

What are the 5 purine analogs? (one bold)

A
  1. Clofarabine
  2. Fludarabine
  3. Mercaptopurine (6-MP)
  4. Nelarabine
  5. Pentostatin
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20
Q

What is “primary induction therapy”?

A
  • The main treatment that provides the best possible outcome
  • Also called first-line therapy
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21
Q

What is neoadjuvant therapy?

Give an example

A
  • Treatment given BEFORE primary induction therapy in order to improve outcome
  • E.g., Chemo or radiation to shrink a tumor before surgery
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22
Q

What is adjuvant therapy?

A

•Additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse

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23
Q

What occurs in G1?

A

Synthesis of components needed for DNA synthesis

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24
Q

What occurs in S phase?

A

Synthesis of DNA

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25
What occurs in G2?
Synthesis of components needed for mitosis
26
What happens in M phase?
Mitosis
27
What happens in G0?
Resting phase of cell cycle
28
Where are the four cell cycle checkpoints?
1. G1 to S 2. End of S 3. G2 to M 4. End of M
29
Why is the cell cycle stuff important for this topic?
Many antineoplastics are either cell cycle specific or cell cycle non-specific
30
What are the 7 categories of drugs that are cell cycle specific?
1. Antimetabolites 2. Antitumor antibiotic - Bleomycin 3. Taxanes 4. Vinca alkaloids 5. topoisomerase I inhibitors 6. Topoisomerase II inhibitors 7. enzymes
31
What phase of the cell cycle do antimetabolits work on?
S phase
32
What phase of the cell cycle does bleomycin work on?
S-G2 phase
33
What cell cycle phase do taxanes work on?
M phase
34
What cell cycle phase do vinca alkaloids work on?
M phase
35
What phase do topoisomerase I inhibitors work on?
S-G2 phase
36
What cell cycle phase do Topoisomerase II inhibitors work on?
S-G2
37
What are the 4 categories of cell cycle nonspecific agents?
1. Alkylating agents 2. anthracyclines 3. antitumor antibiotics (except bleomycin) 4. platinum analogs
38
What is "growth fraction"?
Ratio of proliferating cells to resting cells
39
What is growth fraction a determinant of?
Responsiveness to chemotherapy
40
What are 4 examples of cells with high growth fractions?
1. •Bone marrow 2. •GI tract 3. •Hair follicles 4. •Sperm-forming cells
41
What is the smallest detectible tumor mass and cell count?
1 gram One billion cells
42
How does Burkitt lymphoma respond to chemotherapy?
Burkitt lymphoma is an example of a high growth fraction neaplasm, and is thus cureable by chemotherapy.
43
How does colorectal carcinoma, a low growth fraction neoplasm, respond to chemotherapy?
Poorly, as is typical of low growth fraction neoplasms
44
How can the growth fraction of solid tumors be increaseD?
Reduction of the tumor burden by surgery or radiation
45
What percent of cells does a three-log kill eliminate?
99.9%
46
Efficacy vs toxicity must be carefully considered in antineoplastic therapy. What are five example of factors to consider?
* Renal and hepatic function * Bone marrow reserve * General performance status * Concurrent medical problems * Patient willingness
47
Describe what is meant by "primary resistance". What is this thought to be due to?
* An absence of response on the first drug exposure * Thought to be due to genomic instability
48
Acquired resistance develops in response to exposure to a given antineoplastic agent. Often highly specific to a single drug, or class of drugs, and is usually due to an increased expression of one or more genes What are four examples of single agent resistance pathways?
1. •decreased drug transport into cells 2. •reduced drug affinity due to mutations or alterations of the drug target 3. •increased expression of an enzyme that causes drug inactivation 4. •increased expression of DNA repair enzymes for drugs that damage DNA
49
What is the important example of a method by which multidrug resistance occurs? What gene is associated with this?
•The P-glycoprotein is an ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells -(MDR1 gene)
50
What are five drugs that are especially prone to ATP-dependent transport resistance?
1. anthracyclines 2. vinca alkaloids 3. etoposide 4. paclitaxel 5. dactinomycin
51
What is the major limiting factor in tx of cancer with chemo?
Lack of specificity, hits cells we would prefer they not
52
What are the major tissue sites of chemo toxicity? Give examples
* Rapidly proliferating normal tissues (tissues with high growth fractions) are the major sites of toxicity * bone marrow, gastrointestinal tract, hair follicles, buccal mucosa, sperm forming cells
53
Many antineoplastics are themselves mutagenic and can give rise to secondary neoplasms years after therapy. What is an example of this?
Alkylating agents have been shown to cause AML and ALL
54
What are five common adverse effects that occur during therapy with nearly all **classic** antineoplastic agents?
* Vomiting * Fatigue * Stomatitis * Alopecia * Nausea
55
What are three other common adverse effects of the classic antineoplastic agents?
* Myelosuppression – can lead to impaired wound healing and predisposition to infection * Low sperm counts and azoospermia * Depressed development of children exposed to antineoplastic agents
56
In chemotherapy it is important to take steps that limit adverse effects. One way to do this by selecting a route of administration that limits toxicity. What are some pharmacological agents for reducing toxicity? Oh, also have the patient rest and recover.
* Hematopoietic agents for neutropenia, thrombocytopenia, and anemia * Serotonin receptor antagonist (ondansetron) and other drugs for emetogenic effects * Bisphosphonates to delay skeletal complications
57
Which nitrogen mustard is the most widely used alkylatin agent and one of the most emetogenic agents?
Cyclophosphamide
58
What is the MOA for alkylating agents?
Form covalent linkages with DNA
59
Cyclophosphamide is a prodrug that is degraded to 4-hydroxycyclophosphamide and aldophosphamide. Aldophosphamide is further degraded to a toxic metabolite. What is this metabolite and what is it known for causing?
•Acrolein: causes hemorrhagic cystitis
60
What is used as prophylaxis for the acrolein induced cystitis?
Mesna - inactivates acrolein
61
Systemic toxicities d/t alkylating agents are dose related. What can happen at the site of injection?
Direct vesicant effects and tissue damage. (Oral admin is the ticket)
62
Many alkylating agents produce acute toxicity, such as nausea and vomiting within 30-60 minutes. This can be pretreated with serotonin antagonists. What are some examples of delayed toxicities from alkylating agents.
1. bone marrow suppression with leukopenia 2. thrombocytopenia 3. nephrotoxicity 4. alopecia 5. mucosal ulceration 6. intestinal denudation
63
What is one specific delayed toxicity for cyclophosphamide?
Hemorrhagic cystitis
64
What are two delayed toxicities specific to cisplatin?
renal tubular damage ototoxicity
65
What is a specific delayed toxicity associated with busulfan?
Pulmonary Fibrosis
66
What are the three major types of antimetabolites? What is one bolded drug from each category?
**1.Folic acid analogs (methotrexate)** **2.Pyrimidine analogs (5-Fluorouracil)** **3.Purine analogs (6-mercaptopurine)**
67
What is the MOA for the antimetabolites?
Structural analogs to compounds necessary for cell proliferation that block or subvert pathways that are involved in or lead to cell replication.
68
So, based on their MOA, what part of the cell cycle do the antimetabolites work at?
S
69
What is the specific MOA of methotrexate?
Inhibits dihydrofolate reductase (DHFR)
70
What are three indications for use of methotrexate? Describe the dosing as high or low for each.
* Cancer - High dose * Rheumatoid arthritis - Low dose * Psoriasis - Low dose
71
In the event of an accidentaly methotrexate overdose, how would you treat the patient?
**Leucovorin -** allows reduced folate to bypass the DHFR
72
What is the prototype pyrimidine structural analog?
5-Fluorouracil
73
5-FU is a prodrug, what are the active components, and what do they do? 3
1. FdUMP - covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate. 2. FdUTP - incorporated into DNA 3. FUTP - incorporated into RNA
74
What is the purine structural analog?
**•6-Mercaptopurine (6-MP)**
75
What are the MOA of 6-Mercaptopurine (6-MP)?
* Inhibition of several enzymes of de novo purine nucleotide synthesis * Incorporates into DNA and RNA
76
Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase via first pass effect. What medication must we use caution with when considering using 6-MP? How does this change the dosing for oral and IV 6-MP?
* Allopurinol - commonly used to prevent hyperuricemia d/t tumor cell lysis, will result in increased levels of 6-MP, since it is a xanthine oxidase inhibitor. * Must reduce the oral 6-MP dose by 50 - 75% when taking with allopurinol. * IV dosing is unaffected since not subject to first pass metabolism. (xanthine oxidase is in the liver)
77
The antimetabolite drugs have relatively little acute toxicity after initial dose, and are cell cycle specific, working on the S-phase. What are the three common routes of administration?
Oral IV Intrathecal
78
When would you want to do an intrathecal administration of methotrexate?
When there is invasion of the CNS by neoplasm
79
In addition to diarrhea, nausea, and vomiting, what are 5 more ADR's caused by the antimetabolites?
1. Immunosuppression 2. thrombocytopenia 3. leukopenia 4. hepatotoxicity
80
What are the prototype vinca alkaloids?
**Vinblastine and Vincristine**
81
What are two general ADRs of the vinca alkaloids?
Alopecia myelosuppression
82
Vincristine has some additional ADRs beyond the alopecia and myelosuppression of the vinca alkaloids. What are these? 4
​Neurotoxicity 1. numbness and tingling of the extremities 2. loss of DTRs 3. motor weakness 4. autonomic dysfunction
83
As mentioned previously the vinca alkaloids are associated with myelosuppression. Which one of the two prototypes is this more common with?
Vinblastine more than vincristine
84
What is the mechanism of action for the vinca alkaloids?
Bind to •β-tubulin and ***_inhibit_*** microtubule assembly
85
Are vinka alkaloids cell cycle specific?
Yes. They inhibit mitosis (M phase)
86
What is the MOA for taxanes?
Bind to β-tubulin and ***_stabilize_*** microtubule assembly
87
Based on their MOA, are taxanes cell cycle specific?
Yes, they work on the M-phase
88
What ADRs are associated with paclitaxel? 2
1. Hypersensitivity reactions in hands and toes 2. Change in taste
89
What is the MOA of the camptothecins?
Inhibition of type I topoisomerase
90
What does type I topoisomerase do?
cuts one strand of dsDNA, relaxes the strand and reanneals it.
91
What does Topoisomerase II do?
Cuts BOTH strands of dsDNA simultaneously to wind and unwinds DNA supercoils.
92
What are two inhibitors of type II topoisomerase?
Epidophyllotoxins - **etoposide** Anthracycline antibiotics - **doxorubicin**
93
Are the topoisomerase inhibitors cell cycle specific?
Yes, except for anthracyclines which are CCNA. They are primarily S phase, but also G1 and G2
94
What are the four major antineoplastic antibiotics? 2 BOLD
1. anthracyclines - **doxorubicin** 2. **Bleomycin** 3. dactinomycin 4. mitomycin
95
What are the main effects of the antitumor antibiotics?
mainly on DNA
96
All the antineoplastic antibiotics are products of various species of what bacterial genus?
streptomyces
97
What are the MOA of doxorubicin?
1. Inhibit topoisomerase II 2. Intercalate DNA 3. Oxygen free radicals cause single and double strand DNA breaks
98
Based on the MOA of doxorubicin, is it cell cycle specific?
Cell cycle nonspecific - but cycling cells are more susceptible.
99
What ADRs are associated with doxorubicin?
1. significant cardiotoxicity d/t free radical production 2. cumulative cardiac dmg leads to arrhythmias and heart failure
100
What is the MOA of bleomycin?
Free radical production leading to single and double stranded DNA breaks
101
Is bleomycin cell cycle specific?
yes - G2 arrest
102
What are the ADRs associated with Bleomycin?
1. minimal myelosuppression 2. significant pulmonary toxicity (usually presents as pneumonitis with cough, dyspnea and dry inspiratory crackles.
103
What is the prototype antineoplastic enzyme drug?
L-aspariginase
104
What is the MOA for L-asparaginase?
hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
105
So, cells can synthesize their own amino acids, why then is L-asparaginase useful?
Acute lymphoblastic leukemia (ALL) cells lack the enzyme asparagine synthetase and thus require an exogenous source of L-asparagine.
106
Is L-asparaginase cell cycle specific?
Yes - G1
107
What are the acute ADRs associated with L-asparaginase?
1. Acute hypersensitivty reaction
108
What are the delayed toxicities associated with L-asparaginase?
1. Increased risk of clotting and bleeding 2. pancreatitis 3. CNS toxicity 1. lethargy 2. confusion 3. hallucinations 4. coma
109
What are the categories of miscellaneous antineoplastic agents? 8
1. Substituted Urea 2. Differentiating agents 3. Biological response modifiers 4. Immunomodulators 5. protein tyrosine kinase inhibitors 6. mTOR inhibitors 7. proteosome inhibitors 8. monoclonal antibodies
110
The BCR-ABL fusion protein results from the t(9:22) translocation and is found in 95% of patients with CML. What is the main drug we use on this?
Imatinib (Gleevec)
111
What is the MOA of Imatinib?
1. A small molecule inhibitor of the ABL tyrosine kinase 2. Can also inhibit the RTKs - PDGFR and c-KIT
112
When mutated, overexpressed, or structurally altered, tyrosine kinases can become potent oncoproteins. Aberrant tyrosine kinase activity can occur in receptor tyrosine kinases or cytoplasmic kinases, and has been identified in many human neoplasms. What do we use to target the extracellular RTK? How about the cytoplasmic kinases?
Extracellular - mabs Intracellular - nibs
113
What is the MOA of erlotinib and gefitinib?
Inhibit epidermal growth factor receptor (EGFR), an RTK
114
What toxicities are erlotinib and gefitinib known for?
Dermatologic toxicities - acneform rash
115
What epidermal growth factor receptor is expressed on 25-30% of breast cancers?
HER2/neu
116
What drug do we use to inhibit HER2/neu?
Trastuzumab
117
What ADR is associated with Trastuzumab? What does this mean for us in clinical practice?
Cardiovascular complications including decreased LVEF and heart failure. Must get baseline CV measurements prior to treatment, and monitor heart function periodically through therapy.
118
Bevacizumab is used in tx of colorectal and lung cancers. What is its target and what does it down regulate?
VEGF - This antibody is against the ligand rather than the receptor. Downregulates angiogenesis
119
Cetuximab is used in tx of colorectal, lung, pancreatic and breast cancers. What is its target?
EGFR - tyrosine kinase
120
Rituximab is used in tx of non-hogkin's lymphoma, what is its target antigen? What is that antigens function?
CD20 - proliferation and differentiation
121
In acute promyelocytic leukemia granulocytic maturation is inhibited by the t(15;17) translocation which creates the fusion protein PML-RARα. What drug do we use to treat this?
Tretinoin (all-trans-retinoic acid ATRA)
122
What is the MOA of Tretinoin?
* binds to the PML-RARα fusion protein and antagonizes the inhibitory effect on the transcription of target genes * Within 1-2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die
123
What are the ADRs of Tretinoin?
•Vitamin A toxicity and retinoic acid syndrome are common adverse effects
124
Biological response modifiers are asgents that stimulate or suppress the immune system to help the body fight cancer. What are the two bio response molecules we discussed?
Interferons Interleukin-2
125
What is the MOA of Interferon?
Inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, augment cytotoxicity of lymphocytes for target cells.
126
ADR's of interferon?
bone marrow depression neutropenia anemia renal toxicity edema arrhythmias flu-like syndrome
127
MOA for Interleukin-2?
Increase cytocoxic killing by T cells and NK cells
128
What is the major toxicity associated with IL-2?
Capillary leak syndrome
129

Heme/Lymph - Exam 1 (5 decks)

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