anticancer Flashcards
1
Q
What is cancer?
A
Growth from pre-existing tissues characterized by uncontrolled proliferation of cells.
2
Q
What happens to normal cells to form cancer cells?
A
They lose normal regulatory mechanisms that control growth and multiplication.
3
Q
What are the two types of tumors?
A
- Benign: localized, rapid growth, not life-threatening, not transplantable.
- Malignant: invasive, can form metastasis, transplantable.
4
Q
Define metastasis.
A
Formation of tumors in parts of the body remote from the original tumor.
5
Q
What are the three main approaches to deal with established cancer?
A
- Surgery
- Radiation
- Chemotherapy
6
Q
What is a significant disadvantage of cancer chemotherapy?
A
The maximum effective dose is often close to the point of systemic toxicity.
7
Q
True or False: Chemotherapy drugs are selective and only target cancer cells.
A
False
8
Q
What are the toxic effects of chemotherapy drugs?
A
Toxic to normal cells as well as cancer cells, can alkylate proteins, macromolecules, and DNA.
9
Q
What is the risk associated with antineoplastic drugs that interfere with cell division?
A
Risk of inflicting serious damage to rapidly proliferating organs and tissues.
10
Q
What is monotherapy in cancer treatment?
A
Use of a single drug to treat cancer.
11
Q
What is the benefit of using combination therapy in cancer treatment?
A
Better results than single drug therapy, reduction of toxic effects, delay of resistance.
12
Q
What do alkylating agents contain?
A
Highly reactive electrophilic groups.
13
Q
How do alkylating agents prevent replication and transcription?
A
By covalent bonding with nucleophilic groups in DNA and RNA.
14
Q
What historical observation led to the use of mustard gas in cancer treatment?
A
Mustard gas was found to be highly cytotoxic during World War II.
15
Q
What is nitrogen mustard used for?
A
Initially for Hodgkin’s disease and later in the treatment of acute leukemias in children.
16
Q
What type of crosslinking can alkylating agents cause?
A
- Intrastrand crosslinking
- Interstrand crosslinking
17
Q
What is chlormethine (mechlorethamine)?
A
A nitrogen mustard used medicinally in 1942 that causes DNA crosslinking.
18
Q
What is the mechanism of action of chlormethine?
A
Causes intrastrand and interstrand crosslinking, preventing DNA replication.
19
Q
What is the active form of cyclophosphamide?
A
Phosphoramide mustard.
20
Q
What is busulfan known for?
A
A bifunctional alkylating agent with selective immunosuppressive effects on bone marrow.
21
Q
What are nitrosoureas used for?
A
Useful against malignancies of the CNS due to their lipophilicity.
22
Q
What is the structure unit required for the optimum activity of nitrosoureas?
A
2-chloroethyl-N-nitrosoureido group.
23
Q
What is the significance of the aziridinium ion in alkylating agents?
A
It can cross-link DNA strands.
24
Q
What is the role of carbamoylating agents in nitrosoureas?
A
They react with lysine residues on proteins and may inactivate DNA repair enzymes.
25
Fill in the blank: The most commonly used alkylating agent is _______.
Cyclophosphamide
26
What is the relationship between alkylating agents and DNA repair enzymes?
Alkylating agents can inactivate DNA repair enzymes.
27
What is Lomustine?
N'-2-chloroethyl-N-cyclohexyl-N'-nitrosourea (CCNU)
## Footnote
Lomustine is used as an alkylating agent in cancer treatment.
28
What is Carmustine?
N',N-bis(2-chloroethyl)-N'-nitrosourea (BCNU)
## Footnote
Carmustine is also an alkylating agent used in chemotherapy.
29
What is Semustine?
N'-2-chloroethyl-N-4-methylcyclohexyl-N'-nitrosourea (MeCCNU)
## Footnote
Semustine is another alkylating agent related to nitrosoureas.
30
True or False: The activity of nitrosourea can be due to the formation of aziridinium ion as an alkylating agent.
False
## Footnote
The required electrophiles are less available due to their position on amide nitrogen.
31
What is Dacarbazine?
A prodrug activated by demethylation in the liver
## Footnote
It decomposes to form a methyldiazonium ion which alkylates guanine groups.
32
What is Temozolomide used for?
FDA approved anticancer drug for brain cancer
## Footnote
It crosses the blood-brain barrier and is activated at physiological pH to methyl diazonium salt.
33
What is Mitomycin C?
A natural compound obtained from Streptomyces caepitosus
## Footnote
It was discovered in 1950 and is activated in the body to form an alkylating agent.
34
What type of links does Cisplatin form with DNA?
Intrastrand links at N-7 and O6 of adjacent guanine molecules
## Footnote
This causes localized unwinding of the DNA double helix.
35
What is the mechanism of action of CC1065?
Binds to the minor groove of DNA and alkylates adenine bases
## Footnote
It is 1000 times more active than cisplatin in vitro.
36
What is the main characteristic of antimetabolites?
Compounds closely related in structure to a cellular precursor molecule
## Footnote
They interfere with the formation or utilization of normal cellular metabolites.
37
Which phase of the cell cycle do most antimetabolites act on?
S phase
## Footnote
This is when DNA replication occurs.
38
What is 6-mercaptopurine?
A purine analog that requires bioactivation for its activity
## Footnote
It interacts with many enzymes involved in cell division.
39
What is the role of Allopurinol?
A xanthine oxidase inhibitor used to treat hyperuricemia
## Footnote
It can be administered with 6-mercaptopurine to enhance its potency.
40
What does 5-fluorouracil inhibit?
Thymidylate synthetase
## Footnote
This enzyme converts 2-deoxyuridylic acid to thymidylic acid.
41
What is the action of Methotrexate?
Inhibits dihydrofolate reductase (DHFR)
## Footnote
This results in reductions in nucleic acid base synthesis.
42
Fill in the blank: The fluorine in 5-fluorouracil blocks the conversion of uridylate to _______.
thymidylate
## Footnote
This leads to diminished DNA biosynthesis.
43
What is the primary mechanism of action for aminopterin and methotrexate?
They inhibit the binding of folic acid to dihydrofolate reductase (DHFR)
## Footnote
This results in reductions in the synthesis of nucleic acid bases, particularly the conversion of uridylate to thymidylate.
44
Which drug is more selective, aminopterin or methotrexate?
Methotrexate (amethopterin)
## Footnote
Both drugs show high folic acid antagonism.
45
What is the role of dihydrofolate reductase in nucleic acid synthesis?
It reduces 7,8-dihydrofolic acid into 5,6,7,9-tetrahydrofolic acid, a co-enzyme for thymidylate synthase.
46
How does methotrexate bind to the enzyme folate reductase?
It binds more strongly than natural substrate (folic acid) due to NH instead of OH and electron release NCH3.
47
What is the clinical use of amethopterin (methotrexate)?
It is used for treating acute leukemia in young adults.
48
What is a notable side effect of methotrexate treatment?
Resistance develops to the drug over time.
49
True or False: Aminopterin and amethopterin are toxic to most bacteria or protozoa.
False
## Footnote
They have little toxicity for most bacteria or protozoa.
50
What is the action of trimethoprim?
It inhibits dihydrofolate reductase and is used as an antibacterial.
51
From which sources are many anticancer agents derived?
Natural sources, particularly microbial sources like the soil fungus Streptomyces.
52
What are common mechanisms by which antineoplastic antibiotics target DNA?
Intercalation, alkylation, and strand breakage.
53
Define intercalation in the context of DNA.
It is the process by which a planar molecule inserts itself between adjacent base pairs of DNA, causing local unwinding.
54
What stabilizes the drug-DNA interaction during intercalation?
Ionic bonds, van der Waals interactions, and hydrogen bonds.
55
What effect does intercalation have on DNA?
It causes a local bend or kink, often inhibiting normal DNA function.
56
What role do topoisomerase enzymes play in DNA function?
They are responsible for unwinding and relaxing DNA for transcription.
57
What are the two major types of topoisomerase enzymes?
Topoisomerase I and Topoisomerase II.
58
What is the structure of actinomycin D?
It contains a phenoxazone chromophore and pentapeptides bound through an amide linkage.
59
How does dactinomycin inhibit DNA function?
By partial intercalation between adjacent guanine-cytosine bases.
60
What is the primary effect of dactinomycin on RNA synthesis?
Inhibition of RNA-directed RNA synthesis and specifically RNA polymerase.
61
What class of antibiotics are anthracyclines derived from?
They are derived from Streptomyces peucetius.
62
List the five anthracyclines used clinically in the United States.
* Doxorubicin
* Daunorubicin
* Idarubicin
* Epirubicin
* Valrubicin
63
What is the mechanism of action for anthracyclines?
Intercalation followed by inhibition of topoisomerase II, leading to strand breakage.
64
What is the structure of vinca alkaloids?
They consist of a catharanthine moiety and a vindoline moiety.
65
What is the primary action of vinca alkaloids in cells?
They disrupt the formation and function of the mitotic spindle.
66
What is the origin of taxanes like paclitaxel?
They are isolated from the bark of the Pacific yew tree.
67
What is the role of protein kinases in cellular signaling?
They catalyze phosphorylation reactions on protein substrates.
68
How many protein kinases are estimated to be in a cell?
500-2000.
69
What are the two main types of protein kinase inhibitors?
* Type I inhibitors
* Type II inhibitors
70
What is the action of Type I inhibitors?
They act on the active conformation of the enzyme.
71
What is the key structural feature of gefitinib?
It has a 4-anilinoquinazoline structure.
72
How is gefitinib metabolized?
By cytochrome P450 enzymes.
73
What is a notable chemical property of gefitinib?
The secondary amine and electron-donating substituents are important for activity.
74
What effect does blocking metabolism have on drug half-life?
Improves the half-life of the drug
75
What is the IC50 value of Gefitinib (Iressa)?
5 nM
76
What is the effect of the fluoro substituent in Gefitinib?
Blocks para-hydroxylation of the aromatic ring
77
Why is fluorine used in the design of Gefitinib?
It is similar in size to hydrogen and has no steric effect
78
What is the role of the morpholine ring in Gefitinib?
Increases water solubility
79
Fill in the blank: Gefitinib binds to the ______ binding site.
ATP
80
What is the significance of the aniline ring in Gefitinib's binding interactions?
Occupies the normally vacant hydrophobic pocket opposite the ribose binding pocket
81
What type of inhibitor is Lapatinib?
Reversible tyrosine kinase inhibitor
82
What is the IC50 value of Lapatinib?
2 nM
83
What is the structural characteristic of PKI 166?
Pyrrolopyrimidine structure
84
What type of kinase does Imatinib (Glivec or Gleevec) inhibit?
Hybrid tyrosine kinase (Bcr-Abl)
85
Fill in the blank: Imatinib was initially identified as a ______ inhibitor.
PKC
86
What is the significance of the amide group in Imatinib's binding interactions?
Serves as an anchoring group and orients the molecule
87
What mutation introduces resistance to Imatinib?
T315I mutation
88
What does the piperazinyl group in Imatinib interact with?
Glutamate residue
89
What is the role of cyclin-dependent kinases (CDKs)?
Regulating the cell cycle
90
What type of inhibitors bind to the ATP binding site of CDKs?
Synthetic inhibitors
91
What is Flavopiridol derived from?
Rohitukine, a natural product from an Indian plant
92
What is the clinical trial status of GNF-2?
Currently under study
93
What is the function of FGF-R and VEGF-R in cancer?
Associated with angiogenesis
94
What is the significance of the oxindole structure in SU5416?
Binds to the same region as adenine of ATP
95
What is Vatalanib (PTK787) being studied for?
As a possible treatment for several types of cancer
96
What is anib (SU5416)?
A tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic
## Footnote
It is an experimental stage drug, not licensed for use on human patients.
97
What does oxindole bind to?
The same region as adenine of ATP
98
What is Vatalanib (PTK787 or PTK/ZK)?
A small molecule protein kinase inhibitor that inhibits angiogenesis
99
What types of cancer is Vatalanib being studied for?
Several types of cancer, particularly advanced stage or chemotherapy-resistant cancer
100
Is Vatalanib effective when taken orally?
Yes, it is orally active
101
What are multi-tyrosine receptor kinase inhibitors designed for?
To be selective against a range of tyrosine receptor kinases implicated in tumours
102
What is the likelihood of drug resistance occurring for all kinase targets?
Unlikely
103
What is the equivalent of combination therapy in the context of multi-tyrosine receptor kinase inhibitors?
Poly-pharmacology
104
What are sometimes referred to as 'promiscuous drugs'?
Multi-tyrosine receptor kinase inhibitors
105
What is Sorafenib approved as?
A vascular endothelial growth factor (VEGF-R) kinase inhibitor
106
When was Sunitinib approved?
In 2006
107
Which receptor kinases does Sunitinib inhibit?
VEGF-R, PDGF-R, and KIT receptor kinases
108
When was Pazopanib approved?
In 2009
109
How was the lead compound for Sorafenib found?
By high throughput screening
110
How many compounds were tested to find the lead compound for Sorafenib?
200,000 compounds
111
What was the lead compound's IC50 value?
17 µM
112
What is noted about the methyl substituent in structure II of Sorafenib?
It is optimum for activity and leads to a 10-fold increase in activity
113
What is the effect of the phenoxy group on activity?
It is bad for activity
114
What was the outcome of varying the rings in Sorafenib's design?
Isoxazole ring is not good for activity
115
What is significant about the parallel synthesis in the design of Sorafenib?
1000 analogues synthesised with all possible combinations of rings and substituents
116
What did structure IV of Sorafenib demonstrate?
Slightly increased activity, contradicting results from conventional studies
117
What is the role of the urea functional group in Sorafenib?
Acts as a binding anchor
118
What does HSP 90 do?
Acts as a molecular chaperone and is important for cell survival
119
What is the effect of inhibiting HSP 90?
Likely to lead to cell death
120
Why might targeting HSP 90 be effective against tumor cells?
It may be effective against tumor cells resistant to other drugs
121
What is the lead compound for HSP 90 inhibitors?
Geldanamycin
122
What is crucial to the activity of Geldanamycin?
Urethane group
123
What is a notable characteristic of Geldanamycin?
It has poor solubility and a reactive quinone moiety
124
What are the analogues of Geldanamycin mentioned?
Tanespimycin and Alvespimycin
