INTRODUCTION TO ANTINEOPLASTIC AGENTS Flashcards
(154 cards)
1
Q
Top10 Cancer Sites
Estimated NewCases 2015
EstimatedDeaths 2015
A
1. Breast Cancer (Female) 231,840 40,290 2. Lung and Bronchus Cancer 221,200 158,040 3. ProstateCancer 220,800 27,540 4. Colon and Rectum Cancer 132,700 49,700 5. Bladder Cancer 74,000 16,000 6. Melanoma of the Skin 73,870 9,940 7. Non-Hodgkin Lymphoma 71,850 19,790 8. Thyroid Cancer 62,450 1,950 9. Kidney and Renal Pelvis Cancer 61,560 14,080 10. Endometrial Cancer 54,870 10,170 All Cancer Sites 1,658,370 589,430
2
Q
Alkylating Agents
nitrogen mustards
A
cyclophosphamide
ifosfamide
3
Q
Alkylating Agents
alkyl sulfonate
A
busulfan
4
Q
Alkylating Agents
platinum coordination complexes
A
cisplatin
5
Q
Natural Products
vinca alkaloids
A
vinblastine
vincristine
6
Q
Natural Products
taxanes
A
paclitaxel
7
Q
Natural Products
epipodophyliotoxins
A
etoposide
8
Q
Natural Products
antibiotics
A
bleomycin
doxorubicin
9
Q
Natural Products
eznymes
A
l asparaginase
10
Q
Antimetabolites
folic acid analogs
A
methotrexate
11
Q
Antimetabolites
pyrimidine analogs
A
fluorouracil
12
Q
Antimetabolites
purine analogs
A
mercaptopurine
13
Q
Differentiating agents
A
tretinoin
14
Q
biological response modifiers
A
Interferon-alfa
Interleukin-2
15
Q
Immunomodulators
A
Thalidomide
16
Q
Rescue agents
A
- Leucovorin
* Mesna
17
Q
Protein tyrosine kinase inhibitors
A
dasatinib
erlotinib
imatinib
lapatinib
18
Q
proteasome inhibitors
A
bortezomib
19
Q
monoclonal abs
A
bevacizumab
cetuximab
rituximab
trastuzumab
20
Q
Agents used to minimize adverse effects
A
erythropoietin
filgrastim
ondandetron - serotonin antagonists
21
Q
Cancer Treatment Modalities
A
- Chemotherapy
- Immunotherapy
- Radiation Therapy
- Surgery
- Targeted Therapies
- Transplantation
- Vaccines
- Combinations are the norm
22
Q
Primary Induction Therapy
A
- The main treatment that provides the best possible outcome
* Also called first-line therapy
23
Q
NeoadjuvantTherapy
A
- Treatment given BEFORE primary induction therapy in order to improve outcome
- E.g., Chemo or radiation to shrink a tumor before surgery
24
Q
Adjuvant Therapy
A
•Additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse
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g0 phase
resting
26
m phase
mitosis
27
g1 phase
synthesis of components needed of dna synthesis
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s phase
synthesis of dna
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g2 phase
synthesis of componeneint needed fo ritosis
30
cell phases in order
```
g0
g1
s
g2
m
```
31
checpoints for dna
after g1
befro s phase finishes
end of g2
before m phase finishes
32
Cycling Out of Control
* In many forms of cancer, proteins orpathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated
* For example: p53, CDKs
* Aberrations in checkpoint regulation result in uncontrolled and unregulated cell proliferation
* Cell cycle specific vs. cell cycle nonspecific
33
Antimetabolites (S phase)
5-fluorouracil
6-mercaptopurine
Methotrexate
34
Antitumor antibiotics (S-G2phase)
bleomycin
35
Taxanes(M phase)
Paclitaxel
36
Vincaalkaloids (M phase)
Vinblastine
| Vincristine
37
Topoisomerase II Inhibitors (Epipodophyllotoxins, S-G2 phase
Etoposide
38
Cell cycle nonspecific agents
Alkylating agents
Cyclophosphamide
Ifosphamide
Busulfan
39
Cell cycle nonspecific agents
Anthracyclines
Doxorubicin
40
Cell cycle nonspecific agents
Platinum analogs
Cisplatin
41
Growth Fraction and Tumor Growth Rate
* Growth fraction = the ratio of proliferating cells to resting cells (G0)
* Growth fraction is a determinant of responsiveness to chemotherapy
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Cells with high growth fraction
* Bone marrow
* GI tract
* Hair follicles
* Sperm-forming cells
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higher growth fraction =
shorter doubling time
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lower growth fraction =
longer doubling time
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Growth Fraction and Therapeutic Response
* The initial growth rate of most solid tumors is rapid but decreases over time
* Burkittlymphoma (high growth fraction; curable by chemotherapy) vs. colorectal carcinoma (low growth fraction; chemotherapy has minor activity)
* Some disseminated tumors can be cured by single-agent chemotherapy
* The growth fraction of solid tumors can be increased by reducing the tumor burden (i.e., surgery or radiation)
46
Log Cell Kill Hypothesis
* A fraction (not an absolute number) of cells are killed
* A three-log cell kill eliminates 99.9% of cells:
* 1012to 109cells
* 106to 103cells
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Therapeutic Balance: Efficacy vs. Toxicity
| •Challenge:
provide dose that is therapeutic without being (too) toxic
•Antineoplastic drugs harm both cancerous tissues and healthy tissues
•Not all drug regimens are appropriate for all patients
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Therapeutic Balance: Efficacy vs. Toxicity
| •Factors to consider:
* Renal and hepatic function
* Bone marrow reserve
* General performance status
* Concurrent medical problems
* Patient willingness
49
Primary resistance
* An absence of response on the first drug exposure
| * Thought to be due to genomic instability
50
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
51
Examples of single agent resistance pathways include:
* decreased drug transport into cells
* reduced drug affinity due to mutations or alterations of the drug target
* increased expression of an enzyme that causes drug inactivation
* increased expression of DNA repair enzymes for drugs that damage DNA
52
Multidrug resistance and ATP-dependent Transporters
mechanism
* ATP-dependent transporter gene amplification in neoplasms confers resistance to a broad range of agents used in cancer treatments
* The P-glycoprotein is an ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells (MDR1gene)
53
Multidrug resistance and ATP-dependent Transporters
drugs
Anthracyclines, vincaalkaloids, etoposide, paclitaxel, and dactinomycin
54
Toxicity of Antineoplastic Agents
* The lack of neoplastic specificity for chemotherapeutic drugs is a major limiting factor in the treatment of cancer
* Rapidly proliferating normal tissues (tissues with high growth fractions) are the major sites of toxicity
* bone marrow, gastrointestinal tract, hair follicles, buccalmucosa, sperm forming cells
* Many antineoplastic agents are mutagens themselves and can give rise to neoplasms years after treatment (e.g., alkylating agents have caused AML and ALL)
55
Common Adverse Effects
* Nausea
* Vomiting
* Fatigue
* Stomatitis
* Alopecia
* Myelosuppression –can lead to impaired wound healing and predisposition to infection
* Low sperm counts and azoospermia
* Depressed development of children exposed to antineoplastic agents
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* Nausea
* Vomiting
* Fatigue
* Stomatitis
* Alopecia
Occur during therapy with nearly all classicantineoplastic agents
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Minimizing Adverse Effects
* Choose the route of administration that minimizes systemic toxicity as much as possible
* Pharmacologic agents that help decrease adverse effects
* Hematopoietic agents for neutropenia, thrombocytopenia, and anemia
* Serotonin receptor antagonist (ondansetron) and other drugs for emetogeniceffects
* Bisphosphonates to delay skeletal complications
* Rest and recovery
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inhibit purine ring biosynthesis
inhibit dna synthesis
6 mercaptopurine
| 6 thiglianine
59
inhibit dihydrofolate reduction, block thymidylate and purine synthesis
alimta
| methotrexate
60
block topoisomerase function
```
camptothecins
etoposide
teniposide
dalincrubicin
doxorubicin
```
61
block activites of signaling pathways
protein tyrosine kinase inhibitors
| antibodies
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inhibits ribonucleoside reductase
hydroxyurea
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inhibits thymidylase synthesis
5 flurouracil
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inhibits dna synthesis
```
gemcitabine
cytarabine
fludarabine
2-chlorodeoxyadenosine
clofarabine
```
65
form adducts with dna
platinum analogs
alkylating agents
mitomycin
temozoloide
66
deaminates asparagine
| inhibits protein synthesis
l-asparaginase
67
inhibit function of microtubules
epothilones
taxanes
vinca alkaloids
estramustine
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inducers of differntiation
atra
arsenic trioxide
histone deacelyase inhibitors
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what acts in m phase
mitotic inhibitors
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what acts in g2 phase
bleomycin etoposie and teniposide
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what acts in s phase
dna synthesis inhibitors
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what acts in no the cell cycle
all dna alkylating drugs and most dna intercalating agents
73
Five major types of alkylating agents
1.Nitrogen mustards (cyclophosphamide)
2.Nitrosoureas(carmustine)
3.Alkyl sulfonates(busulfan)
4.Methylhydrazinederivatives (procarbazine)
5.Triazines(dacarbazine)
•Also included are platinum compounds (cisplatin)
74
The nitrogen mustard cyclophosphamide is the most
widely used alkylating agent and one of the most emetogenicagents
75
alkylating agents are cell cycle
nonspecific
76
Alkylating Agents: Mechanism of Action
Alkylating agents form covalent linkages with DNA
intrastrand and cross-linking
77
Biotransformation of Cyclophosphamide
goes to 4 hydroxyphosphamide that is either turned to inactive 4 ketocyclophasophamide by and enzyme or aldophosphamide by cype2b from here it is either inactivated by hepatic aldehyde oxidase to carboxyphosphamide or turned to phosphoramide mustard which is cytotoxic and acrolein which is also cytotoxis (mesna deactivates this one)
78
Acroleincauses
hemmorhagic cystitis
79
mesna
Mesnainactivates acroleinand is used for prophylaxis of chemotherapy-induced cystitis
80
Alkylating Agents: Toxicities
overview
* Systemic toxicities are dose related
* Direct vesicant effects and tissue damage at site of injection (oral administration is of great clinical benefit)
* Many alkylating agents produce acute toxicity, such as nausea and vomiting within 30-60 minutes (pretreat with serotonin antagonist)
* Delayed toxicities include the common side effects of antineoplastics: bone marrow depression with leukopenia, thrombocytopenia, nephrotoxicity, alopecia, mucosal ulceration, intestinal denudation
81
Cyclophosphamide ae
hemorrhagic cystitis
82
Cisplatin ae
renal tubular damage ototoxicity
83
busulfan ae
pulmonary fibrosi
84
Three major types of antimetabolites
1. Folic acid analogs (methotrexate)
2. Pyrimidine analogs (5-Fluorouracil)
3. Purine analogs (6-mercaptopurine)
85
antimetabolites moa
* Structural analogs to compounds necessary for cell proliferation
* Block or subvert pathways that are involved in, or lead to, cell replication (nucleotide and nucleic acid synthesis)
86
antimetabolites are cell cycle specific for what phase
s
87
Methotrexate is a
folic acid analog
88
methotrexate moa
•Inhibits dihydrofolatereductase(DHFR)
so dihydrofolic acid cant become tetrhydrofolic acid
89
methotrexate indications
* Cancer
* Rheumatoid arthritis
* Psoriasis
90
Methotrexate & LeucovorinRescue
* Leucovorin: reduced folatecan bypass DHFR
* Used to rescue normal cells from high-dose MTX
* Antidote for accidental MTX overdose
enters the cycle after methotrexate does its job
91
cut the? into single pieces
pyrimidines,
92
Pyrimidine Structural Analogs
* Prototype: 5-Fluorouracil (5-FU)
| * Prodrug
93
Fluorouracil: Mechanisms of Action
Active compound (FdUMP)
covalently binds thymidylatesynthetaseand blocks de novosynthesis of thymidylate
94
Fluorouracil: Mechanisms of Action
Active compounds (FdUTPand FUTP)
are incorporated into both DNA and RNA, respectively
95
can leucovorin resue fluorouracil
no
96
Purine Structural Analogs
* Prototype: 6-Mercaptopurine (6-MP)
| * Prodrug
97
Purine Structural Analogs moa
* Inhibition of several enzymes of de novopurine nucleotide synthesis
* Incorporates into DNA and RNA
98
Drug Interaction: 6-MP & Allopurinol
* Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase (first pass effect)
* Allopurinol, a xanthine oxidase inhibitor, is often used as supportive care in the treatment of acute leukemiasto prevent hyperuricemiadue to tumor cell lysis
* Simultaneous administration of allopurinol and oral6-MP results in increased levels of 6-MP and increased toxicity
* Reduce oral 6-MP dose by 50-75%; IV dose unaffected
99
Antimetabolites: Pharmacodynamics
* Cell cycle specific (S-phase)
* Relatively little acute toxicity after an initial dose
* Oral, intravenous, intrathecal(methotrexate) are common routes of administration
100
antimetabolites common toxicities
diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, hepatotoxicity
101
VincaAlkaloids drugs
vinblastineand vincristine
102
VincaAlkaloids adverse effects
* Alopecia
* Myelosuppression(vinblastine > vincristine)
* Vincristine exhibits neurotoxicity (numbness and tingling of the extremities, loss of deep tendon reflexes, motor weakness, autonomic dysfunction has also been observed)
103
VincaAlkaloids: Mechanism of Action
* Bind to β-tubulin and inhibit microtubule assembly
| * Cell cycle specific mitosis inhibition (M-phase)
104
Taxanes: Mechanism of Action
* Bind to β-tubulin and stabilizemicrotubule assembly
| * Cell cycle specific mitosis inhibition (M-phase)
105
Taxanes
| •Prototypes
paclitaxeland docetaxel
106
paclitaxel ae
Hypersensitivity reactions in hands and toes, change in taste
107
docetaxel ae
* Greater cellular uptake; retained intracellularlylonger than paclitaxel permitting smaller dose, which reduces AEs
* Hypersensitivity, neutropenia, alopecia
108
taxanes indication
treatment of several solid tumors
109
Type I Topoisomerases cut
one strand of double-stranded DNA, relax the strand, and reannealthe strand
•Inhibitors: Camptothecins(topotecan, irinotecan)
110
Type II Topoisomerases cut
both strands of double-stranded DNA simultaneously to wind and unwind DNA supercoils
•Inhibitors:
•Epipodophyllotoxins(etoposide, teniposide)
•Anthracyclineantibiotics (doxorubicin, daunorubicin)
111
Topoisomerase Inhibitors
| Cell cycle specific
primarily S phase, also G1and G2) –except anthracyclines, which are CCNA
112
Four major antineoplastic antibiotics
1. Anthracyclines(doxorubicinand others)
2. Bleomycin
3. Dactinomycin
4. Mitomycin
113
antitumor antibiotics overview
* Effects are mainly on DNA
| * All of the anticancer antibiotics currently in use are products of various species of the bacterial genus Streptomyces
114
Anthracyclines
drugs
rototype: doxorubicin
115
anthracyclines moa
* Inhibit topoisomerase II
* Intercalate DNA
* Oxygen free radicals bind to DNA causing single-and double-strand DNA breaks
* Cell cycle nonspecific (but cycling cells are most susceptible)
116
anthracyclines ae
* Free radicals are linked to significant cardiotoxicity
| * Cumulative cardiac damage can lead to arrhythmias and heart failure
117
Bleomycin
* MOA: Free radicals cause single-and double-strand DNA breaks
* Cell cycle specific (G2arrest)
* Causes minimal myelosuppression–useful in combination
* Can cause significant pulmonary toxicity (5-10%, usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles)
118
Dactinomycin
* MOA: Intercalates DNA
| * Cell cycle nonspecific
119
Mitomycin
* MOAs: Intercalates DNA; forms free radicals
| * Cell cycle nonspecific
120
Antineoplastic Enzymes
| Prototypes
L-aspariginaseand pegaspargase(PEGylatedaspariginase
121
Antineoplastic Enzymes
| moa
hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
•Cell cycle specific (G1)
122
Antineoplastic Enzymes
| ae
* Acute hypersensitivity reaction
* Delayed toxicities include an increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma
123
Antineoplastic Enzymes
| indication
Targeted therapy for acute lymphoblastic leukemia (ALL)
| •ALL tumor cells lack the enzyme asparagine synthetaseand thus require an exogenous source of L-asparagine
124
The BCR-ABL fusion protein
results from the t(9:22) translocation and is found in 95% of patients with CML
125
Imatinibis a small molecule
inhibitor of the ABL tyrosine kinase and has been hailed as a conceptual breakthrough in targeted chemotherapy
126
Imatinibcan also inhibit
the RTKs PDGFR and c-KIT
127
Tyrosine Kinases and Cancer
* When mutated, overexpressed, or structurally altered, tyrosine kinases can become potent oncoproteins
* Abnormal activation of tyrosine kinases has been found in many human neoplasms
* Aberrant tyrosine kinase activity can occur in receptor tyrosine kinases or cytoplasmic kinases
* Attractive targets for cancer therapy
128
INTRACELLULAR
NIBS
129
extracellular
mabs
130
Erlotiniband Gefitinib
* MOA: Inhibit Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase
* Preferred single-agent first-line therapy for NSCLC patients with somatic activating EGFR mutations
* Produce dermatologic toxicities
131
Inhibtionof HER2/neu
* The epidermal growth factor receptor HER2/neuis expressed on the cell surface of 25-30% breast cancers
* Activation of HER2/neuinduces differentiation, growth, and proliferation
* Trastuzumaband lapatinib
132
trastuxumab and ae
cv complication
133
cv complications withiatpatinib
less frequent
134
alemtuzumab (not red)
Antigen
Cancer
Antigen function
CD52
Chronic lymphocytic leukemia
Unknown
135
bevacizumab
Antigen
Cancer
Antigen function
VEGF
Colorectal, lung
Angiogenesis
136
cetuximab
panitumumab
Antigen
Cancer
Antigen function
EGFR (ErbB-1)
Colorectal, lung, pancreatic, breast
Tyrosine kinase
137
rituximab
ibritumomab
tositumomab
Antigen
Cancer
Antigen function
CD20
Non-Hodgkin’s lymphoma
Proliferation
Differentiation
138
gemtuzumab (no red)
Antigen
Cancer
Antigen function
CD33
Acute myeloid leukemia
Unknown
139
trastuzumab
Antigen
Cancer
Antigen function
HER2/neu
Breast
Tyrosine kinase
140
The t(15;17) translocation creates
Differentiating agents...
the fusion protein PML-RARα, which inhibits granulocytic maturation in APL
141
Tretinoin
differentitating agents
Tretinoin(all-trans-retinoic acid, ATRA) binds to the PML-RARαfusion protein and antagonizes the inhibitory effect on the transcription of target genes
142
differentiating agents overview
* Within 1-2 days the neoplastic promyelocytesbegin to differentiate into neutrophils, which rapidly die
* One of the most successful uses of targeted therapy in cancer
* Vitamin A toxicity and retinoic acid syndrome are common adverse effects
143
Biological Response Modifiers
•Agents that stimulate or suppress the immune system to help the body fight cancer
Interferons
interluekin2
144
interferons
moa
•MOA: Inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells
145
interleukin2
* MOA: Increases cytotoxic killing by T cells and NK cells
| * Major toxicity is capillary leak syndrome
146
interferons ae
•Adverse effects: bone marrow depression, neutropenia, anemia, renal toxicity, edema, arrhythmias, and flu-like symptoms
147
draw chemoman
now
148
mucositis
•Methotrexate, melphalan
149
peripherneuropathy
•Vincristine
150
pulmonary fibrosis
•Bleomycin, busulfan
151
otoxicity
•Cisplatin
152
nephrotoxicity
•Cisplatin, cyclophosphamide
153
hemorrhagic cystitis
•Cyclophosphamide, ifosfamide
154
cardiotoxicity
* Doxorubicin, daunorubicin
| * Trastuzumab
