Anticancer agents Flashcards
1
Q
LO
A
Describe the processes that can lead to cancer formation
- viral and cellular oncogenes
- chromosomal aberrations
- mutagenesis
Explain the molecular basis of action of current anticancer agents, with particular emphasis on
- new agents against specific molecular targets
- cytotoxic agents targeted at DNA replication
2
Q
What is selective toxicity and how is it involved with cancer therapy?
A
The use of chemical agents that are toxic to an invading organism or cell, which do not affect the host.
This is clearly a problem for developing anti-cancer drugs as the diseased cells have similarproperties to normal cells (especially those in bone marrow, hair, GI mucosa and skin).
We need to look for “windows of opportunity” where cancer cells are especially vulnerable
3
Q
PTEN is an important tumour suppressor gene
Want only green cells to be used in therapy
Helps find drug targets that only effects cancerous cells
A
4
Q
What two things lead to tumour cells?
A
Inhibition of tumour suppressor gene and the activation of oncogene leads to tumour cells
5
Q
What is precision medicine and how is it used?
A
Precision medicine patients with tumours that share the same genetic change receive the drug that targets that change, no matter the type of cancer
6
Q
Tell me about Transcriptomic profiling and how it is used in cancer therapy
A
defines 2 major subgroups of MYCN non-amplified Neuroblastomas for precision prognosis and therapy stratification
7
Q
Stats for cancer in the UK
A
Don’t need to learn but useful information to be aware of
8
Q
What are the two important mechanisms for maintaining cell growth and how are they effected in tumours?
A
Organs and tissues are maintained at appropriate size.
Control mechanisms: 2 important cellular processes must balance each other perfectly – proliferation and apoptosis.
Normal cells have a balance between proliferation and apoptosis. In tumour cells there is more proliferation and less apoptosis which means the cell number increases. This difference +oncogene and -TSG
Invasions and Metastasis leads to a malignant cancerous cell
9
Q
What is proliferation?
A
Proliferation refers to the growth and reproduction of cells.
10
Q
What is apoptosis?
A
Apoptosis (cell suicide) is the mechanism by which old or damaged cells normally self-destruct.
11
Q
Tell me about the processes involved in normal cells developing into cancerous cells
A
Neoplasia excess proliferation, without relation to normal growth and repair. Growth may be fast, but rarely exceeds that in the fastest growing tissues.
Benign proliferate locally and retain tissue characteristics, defined boundary.
Malignant not encapsulated, ill-defined edge, projections extend into surrounding tissues, less well differentiated than the cells of origin.
Spread by invading surrounding tissues – carried to other parts of the body) metastases (secondary tumours)
12
Q
Compare a malignant verses benign tumour
A
13
Q
Explain the differences between the Karyotypes of cancerous vs normal chromosomes
A
Karyotype illustrating structural abnormalities in cancer
Different chromosome numbers
Normal has only one colour whereas cancerous have multiple
14
Q
What is a mutation and what are they used to define?
A
A mutation is a change in the normal base pair sequence
Commonly used to define DNA sequence changes that alter protein function
15
Q
What are the two main types of mutation
A
Germline mutation
Somatic mutation
16
Q
Whats a germline mutation?
A
A change in the DNA sequence that can be inherited from either parent
Every cell in the body has this mutation
17
Q
Whats a somatic mutation?
A
A change in the DNA sequence in cells other than sperm or egg
The mutation is present in the cancer cell and its offspring, but not in the patient’s healthy cells
This only happens in the tumour cells
18
Q
If you have cancer, its usually because someone in your family has had cancer? True or false
A
False
19
Q
Whats the importance of somatic DNA changes in human cancer?
A
Only 5 –10% of cancer cases have a clear hereditary component,
e.g., BRCA1 and BRCA2 in breast cancer
Even in those cases where susceptibility is clearly inherited, somatic changes are required for cancer to develop
20
Q
Tell me about Hereditary predisposition and cancer
A
Some families are more susceptible to getting certain cancers. Remember you can’t inherit cancer it’s just that you are maybe more susceptible to getting it.
21
Q
Who can get breast cancer and what mutations are involved in this cancer?
A
5-10% cases have BRCA1/BRCA2 mutations
10-20% cases have family history, no BRCA1/BRCA2 mutations
Most cases have no BRCA1/BRCA2 mutations, family clusters of cases persist
22
Q
Origins of cancer
A
23
Q
What are the four levels of tumour heterogeneity?
A
24
Q
What are the two types of cancer genes?
A
Tumour suppressor genes (checkpoints)
Oncogenes
25
Explain the role of tumour suppressor genes and oncogenes in cancer
26
ASPP2 knockdown cooperates with oncogenic RAS activation to promote invasion
27
A model for colon cancer
28
Explain how the P53 gene acts as an important TSG?
29
Which of the following is not a tumour suppressor gene?
* Rb
* p53
* APC
* RAS
* BRCA
RAS
This is an important oncogene
30
Snapshot of Ras signalling
31
Whats the overview of what happens in Ras signalling
EGFR upon activation can cause Ras from GDP --\> RAS GTP
RAS is the active form which causes downstream signalling of Rat and PI3K
32
Tell me about the **KRAS** gene and what a mutation in this gene can lead to?
The KRAS gene codes for a signalling molecule
Mutations in KRAS are present in many cancers, including pancreatic cancer, colon cancer.
You have to look for the mutations by comparing healthy DNA sequence with tumour DNA sequence
33
34
Tell me how a **heterozygous mutation** would be identified?
35
KRAS mutations, how common?
This pattern of mutations across the gene is like that of other members of the Ras family and has the signature of an **oncogene** – clusters of mutations which only occur in specific regions of the gene. This means the protein will still function but, in this case, will encourage inappropriate cell growth as the protein is permanently “switched on”, or activated.
36
Whats the impact of KRAS mutations?
What does the gene help with, when is it activated. inactivated?
KRAS helps to transmit external growth signals to the cell nucleus, driving normal cell growth. It is:
* Activated when it binds GTP
* Inactivated or “switched off” when GTP is hydrolysed to GDP
37
What does a mutated KRAS gene encode?
The mutated gene encodes proteins with **reduced GTPase activity**. These proteins are locked into a GTP active state – continuously sending cell growth signals.
38
What is the difference between this two histogram?
The key difference between KRAS and RB1 is the **range and frequency of mutations.**
RB1 has 194 different mutations many of which truncate the encoded protein. For example, 88 (28%) are nonsense substitutions which result in the protein being truncated. 53 (17%) are deletions that cause a frameshift and truncate the protein.
39
Tell me about mutations in tumour suppressor genes and what could occur if they stop functioning?
TSG as a brake – to stop it working you can cut the brake cable anywhere and it will stop functioning. In the case of an oncogene or accelerator, there are only a limited number of ways for it to become stuck “on”. Therefore the oncogene KRAS has a limited number of gene regions which can acquire mutations (and still function albeit inappropriately) and why a TSG such as RB1 has so many different regions of acquired mutations.
40
Mutations can also be caused by **Carcinogens**
Name the different carcinogens and what is included under each one?
**Ionising radiation**
* X Rays, UV light
**Chemicals**
* tar from cigarettes
**Virus infection**
* HPV for cervical cancer
* Epstein-Barr Virus for lymphoma and Nasopharyngeal carcinoma
* Helicobacter Pylori implicated in gastric carcinoma
* Hepatitis B virus, strong association with Liver Cancer
41
Whats the common herbal medicine that may cause liver cancer mutations?
42
List of IARC Group 1 carcinogens
43
Whats the main cancer caused by **UV radiation?**
Tell me about the type of mutations and what could happen
**Malignant melanoma;**
UV-light-induced mutations leave a typical signature of **C\>T or G\>A mutations.**
if these DNA changes occur in critical genes such as **BRAF**, this can lead to inappropriate and sometimes aggressive cell growth and therefore the development of malignant melanoma.
44
Whats the typical cancer caused by tobacco smoke?
Why does cancer arise from smoking and what mutations occur?
**Lung cancer;**
Tobacco smoke contains more than **60 mutagens that bind and chemically modify DNA**. These brand the lung cancer genome with characteristic mutational patterns.
Research has shown that the tobacco smoke carcinogens polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines cause **G\>T mutations**
45
Give an example of a biological factor which can cause cancer?
What happens in this example?
Whats been developed to help combat this?
**HPV is a cause of cervical cancer;**
When HPV enters cells of the cervix proteins made by the virus activate and inactivate oncogenes and tumour suppressor genes respectively. It is like a machine for turning on lots of cancer genes. The image shows a lesion in a human cervical epithelium infected with human papilloma virus (HPV16). Early viral proteins (green) bind to and re-organise the keratin filaments (red) towards the edge of the cell. Cell nuclei are stained with Dapi (blue).
**Vaccination** against HPV dramatically reduces cases of cervical cancer. An HPV vaccine is available, and vaccination and screening programmes are being introduced in the UK.
46
What cancer is obesity associated with?
Bowel and stomach cancer
47
Viral and cellular oncogens
48
Gene amplification
49
For the following chromosomal rearrangements or translocations, how are the proto-oncogenes expressed?
50
What are the hallmarks of cancer?
Hanahan, D.; Weinberg, R. (2000). "The hallmarks of cancer". Cell 100, 57–70
Hanahan, D.; Weinberg, R. (2011). "The hallmarks of cancer: The next generation". Cell 144, 646-674
1. Self-sufficiency in growth signals
2. Insensitivity to antigrowth signals
3. Evasion of apoptosis
4. Limitless replicative potential (telomerase).
5. Sustained angiogenesis
6. Tissue invasion and metastasis.
7. (Genome Instability)
51
Tell me some hallmarks of cancer and some of the emerging hallmarks and enabling characteristics
52
What are some of the therapeutics that target the hallmarks of cancer?
53
Give an example of a chromosomal rearrangement or translocation
54
Tell me about the **philadelphia chromosome** and in what cases it is usually identified in
The Philadelphia chromosome is a reciprocal translocation involving **chromosomes 9 and 22** that is commonly identified in all cases of **chronic myelogenous leukemia (CML)** and 10% of acute lymphotic leukaemia (ALL)
The break points of the translocation create a fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22
55
What does this Bcr-Abl FISH flourescence imaging show?
Red is a PCR gene
Green is an ABL gene
The yellow/ white colour shows fusion (shows translocation event)
56
Tell me about the regulation of the c-Abl and Bcr-Abl tyrosine kinases
57
Tell me about the drug **Gleevec/Glivec (Imatinib; STI 571, CGP57148B)**
Gleevec is a brand-name prescription medication. It's used to treat certain types of blood cancers in adults and children. Gleevec is also used to treat a type of skin cancer and a type of gastrointestinal cancer.
58
Whats an important mutation for resistance amplification and overexpression?
59
State some major imatinib resistance mutations
**T315I**
**E255K**
**H396P**
60
What binds to the active form of Abl and overcomes 14 of 15 of the imatinib-resistant mutants?
61
92% of patients who were resistant or unresponsive to Gleevec acheived a normal white blood cell count after 5 months treatment with **nilotibib** except what mutation?
The **T315I** mutation
62
Activity of imatinib mesylate and the second-generation tyrosine kinase inhibitors nilotinib and dasatinib against a selection of BCR-ABL1 mutants found in patients with CML. All concentrations are shown in nanomoles per millilitre and represent IC50 values.
63
Tell me about some third generation Bcr-Abl inhibitors
64
What is **EGFR** used as a target for?
Explain how it is used as a target
EGFR is used as a target for **cancer therapy** because it is commonly expressed at a high level in a variety of solid tumours and it has been implicated in the control of cell survival, proliferation, metastasis and angiogenesis.
65
What else can be used as targeted therapy?
Monoclonal antibodies
66
The relative frequencies of the various mechanisms of acquired resistance
67
Tell me the different EGFR mutations which are associated with drug resistance and drug sensitivity
68
Response rates to second and third generation EGFR TKIs in clinical trials
69
Tell me about **Second-generation EGFR TKIs**
Second-generation EGFR TKIs form irreversible covalent bonds with the ATP-binding site of EGFR as well as other members of the HER family of receptors (excluding Her3).
70
Tell me about **Third-generation EGFR TKIs**
Third-generation EGFR TKIs specifically target both activating mutations and T790M mutations in EGFR.
71
Tell me about the drug **Vemurafenib** and what process it inhibits
72
Mechanisms of acquired resistance to BRAF-V600E inhibition that led to reactivation of the MAP kinase pathway.
Tell me this pathway
73
What individual(s) recieved the nobel prize for their discovery of cancer therapy by inhibitor of negative immune regulation
74
Name some checkpoints that regulate T cell antigen recognition.
What two are particuarly important
75
Where does checkpoint blockade function?
76
Name some agents used in clinical trials
**Anti-PD-1**
* Nivolumab (BMS)
* Pembrolizymab (Merck)
* Pidilizumab (curetech)
* MEDI-0680 (Medimmune-AZ)
* PDR001 (Novartis)
* Regn2810 (regeneron)
**Anti-PD-L1**
* Atezolimumab (MPDL3280, GNE)
* Durvalumab (MEDI-4736 Medimmune-AZ)
* Avelumab (MSB0010718C EMD Serono)
* MDX-1105 (BMS)
**Multiple other agents in development**
77
PD-1 or PD-L1 blockade stimulates what?
anti-tumour T cell response
78
Broad anti-tumour efficacy of anti-PD-L1/ PD-1 inhibitors: overall response rates
79
What is better than chemo in melanoma?
80
Tell me about **Bevacizumab (Avastin)**
81
Targeted therapy in lung cancer
82
Potential algorithm for incorporating chemotherapies, immunotherapy, and targeted therapies into the management of NSCLC in the future
83
What are the different stages of the cell cycle?
G1 phase: cell prepares for DNA synthesis
S phase: cell generates complete copy of genetic material
G2 phase: cell prepares for mitosis
M phase: replicated DNA is condensed and segregated into chromosomes
G0 phase: resting state
84
With chemotherapy, it is able to target the cell cycle phase specifically and non-specifically. explain each
**Cell cycle phase – specific**
agents with major activity in a particular phase of cell cycle
**Cell cycle phase – nonspecific**
agents with significant activity in multiple phases
85
What does chemotherapy target and what are the side effects due to this?
Chemotherapy targets cells which are **dividing rapidly (highly proliferating)**
Chemotherapy cannot distinguish between normal cells and cancer cells
Healthy Cells which have a high rate of growth and multiplication include cells of the **bone marrow, hair, GI mucosa and skin.**
86
What are the different chemotherapy classes
Alkylating agents
Taxanes
Topoisomerase II inhibitors
Platinum complexes
Anthracyclines
Antimetabolites
Tubulin interactive agents
miscellaneous agents
87
Tell me what is included within each of the chemotherapy classes;
* Alkylating agents
* Taxanes
* Topoisomerase II inhibitors
* Platinum complexes
* Anthracyclines
* Antimetabolites
* Tubulin interactive agents
* Miscellaneous agents
**Alkylating agents**
nitrogen mustards
thiotepa, busulfan
nitrosoureas, mitomycin
procarbazine, dacarbazine
**Taxanes**
paclitaxel, docetaxel
nab-paclitaxel
**Topoisomerase II inhibitors**
etoposide
**Platinum Complexes**
cisplatin, carboplatin
oxaliplatin
**Anthracyclines**
doxorubicin, daunorubicin
idarubicin, mitoxantrone
**Antimetabolites**
methotrexate
purine antagonists
pyrimidine antagonists
**Tubulin interactive agents**
vincristine, vinblastine
**Miscellaneous agents**
bleomycin
asparaginase
hydroxyurea
88
What do the chemotherapy classes prevent and what are the side effects of these drugs?
prevent DNA segregation or incorporated into DNA and effect its synthesis are the two mechanisms by which chemo drugs act
side effects from all these drugs are similar because they cannot distinguish between cancerous cells and normal cells
89
The alkylating agents either spontaneously or after metabolism yield what?
What does this go on to react with?
The alkylating agents either spontaneously or after metabolism yield an **unstable alkyl group**, **_R-CH2+_**, which reacts with nucleophilic centers on proteins and nucleic acids.
In most cases they may be considered to be cell cycle nonspecific agents. Many are bifunctional and can cross-link two DNA chains.
90
Tell me the following about **Mechlorethamine**
1. Chemical nature
2. Mechanism of action
3. Resistance
4. Cell cycle specificity
5. Toxicity
**_MECHLORETHAMINE (Nitrogen mustard, Mustargen, Mustine)_**
**1. CHEMICAL NATURE:** Cl-CH2-CH2-N(CH3)-CH2-CH2-Cl. Decomposes rapidly in water.
**2. MECHANISM OF ACTION:** Bifunctional alkylating agent.
**3. RESISTANCE:** Increased proficiency of DNA repair
**4. CELL CYCLE SPECIFICITY:** Nonphase specific but mitosis and G1 are most sensitive
**5. TOXICITY:** Nausea and vomiting, myelosuppression, local vesicant action
91
Tell me about alkylating agents and their roles
92
Tell me about cis-platin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. It is given by injection into a vei
93
Tell me the following about the antimetabolite **Methotrexate**
1. Mechanism of action
2. Resistance
3. Cell cycle specificity
4. Toxicity
**_Methotrexate_**
**1. MECHANISM OF ACTION:** Analog of folic acid which inhibits dihydrofolate reductase and thereby inhibits one carbon transfers required for nucleic acid synthesis. Selective rescue of normal cells may be achieved with leucovorin (citrovorum factor).
**2. RESISTANCE:**
a. Decreased transport
b. Decreased affinity of target enzyme
c. Gene amplification and increased synthesis of target enzyme
**3. CELL CYCLE SPECIFICITY:** Kills cells in S phase but also slows entry of cells into S phase
**4. TOXICITY:** Myelosuppression, Mucosal ulceration in GI tract, Nausea
94
What are the following analogs of?
## Footnote
**Methotrexate**
**5-FU**
**Cytarabine**
Methotrexate (analog of folic acid)
5-FU (analog of thymine)
Cytarabine (analog of pyrimidine)
95
What does methotrexate inhibit and why is this the case?
Inhibits dihydrofolate reductase
It has a very similar structure to folic acid (bar the methyl group attachment) and folic acid are competitive inhibits of absorption
96
Tell me the following about **5-fluorouracil (5-FU)**
1. Chemical nature
2. Mechanism of action
3. Resistance
4. Cell cycle specificity
5. Toxicity
6. Therapeutic use
7. Metabolism
**_5-FLUOROURACIL (5-FU)_**
**1. CHEMICAL NATURE:** structural analog of thymine
**2. MECHANISM OF ACTION:** 5-fluorouracil is metabolized to ribo and deoxyribonucleoside phosphates. There is inhibition of thymidylate synthetase by 5-fluoro-2'- deoxyuridine-5'-monophosphate. In addition, there is incorporation of 5-fluorouridine triphosphate into RNA.
**3. RESISTANCE:** Multiple mechanisms including increased synthesis or altered affinity of target enzymes, decreased activation and increased catabolism
**4. CELL CYCLE SPECIFICITY:** cells are killed throughout the cell cycle, mainly S phase
**5. TOXICITY:** Myelosuppression, Nausea and vomiting, Anorexia, Alopecia
**6. THERAPEUTIC USE:** GI tract adenocarcinomas, in combination protocols for breast cancer, topical application for premalignant keratoses
**7. METABOLISM:** Similar to uracil after action of dihydrouracil dehydrogenase in the liver.
97
Tell me the following about **Cytarabine (cytosine arabinoside, ara-C)**
1. chemical nature
2. mechanism of action
3. Resistance
4. cell cycle specificity
5. toxicity
6. metabolism
**_CYTARABINE (Cytosine arabinoside, ara-C)_**
**1. CHEMICAL NATURE:** 1-beta-arabinofuranosylcytosine (analog of the pyrimidine nucleoside, cytosine, with substitution of arabinose for ribose)
**2. MECHANISM OF ACTION:** The triphosphate metabolite inhibits DNA polymerase
**3. RESISTANCE:**
a. Decreased kinase activity required for activation
b. Increased inactivation by deaminase
**4. CELL CYCLE SPECIFICITY:** S-phase specific, blocks progression from G1 to S
**5. TOXICITY:** Myelosuppression, Nausea and vomiting
**6. METABOLISM AND EXCRETION:** Excreted chiefly as the noncytotoxic metabolite, uracil arabinoside. Deamination can be inhibited by tetrahydrouridine.
98
Give examples for the following plant alkaloids...
* Vinca alkaloids
* Taxanes
* Podophyllotoxins
* Camptothecan analogs
What do each of them inhibit ?
**Vinca alkaloids:** Vincristine, Vinblastine and Vinorelbine (mitotic inhibitor)
**Taxanes:** Paclitaxel and Docetaxel (mitotic inhibitor)
**Podophyllotoxins:** Etoposide and Tenisopide (inhibition of topoisomerase)
**Camptothecan analogs:** Irinotecan and Topotecan (inhibition of topoisomerase)
99
Tell me the following about **Vinblastine (Velban)**
1. Chemical nature
2. Mechanism of action
3. Resistance
4. Cell cycle specificity
5. Toxicity
**_VINBLASTINE (Velban)_**
**1. CHEMICAL NATURE:** Vinblastine sulfate is the salt of a dimeric alkaloid from the plant Vinca rosea
**2. MECHANISM OF ACTION:** Binds to tubulin and interferes with spindle assembly in mitosis
**3. RESISTANCE:** Decreased cellular uptake or increased efflux
**4. CELL CYCLE SPECIFICITY:** Mitosis, but at high concentrations inhibits S and G1
**5. TOXICITY:** Leukopenia, nausea, and vomiting
100
Tell me the following about **Vincristine (Oncovin)**
1. Chemical nature
2, Mechanism of action
3. Resistance
4. Cell cycle specificity
5. Toxicity
**_VINCRISTINE (Oncovin)_**
**1. CHEMICAL NATURE:** Vincristine sulfate is the salt of a dimeric alkaloid from the plant Vinca rosea.It differs from Vinblastine in the substitution of an aldehyde for a methyl group.
**2. MECHANISM OF ACTION:** Binds to tubulin and interferes with spindle assembly in mitosis
**3. RESISTANCE:** Decreased cellular uptake or increased efflux
**4. CELL CYCLE SPECIFICITY:** Mitosis
**5. TOXICITY:** Numbness and tingling of fingers and toes, hair thinning, minimal myelosuppression
101
Tell me about **Taxol**
Its an anticancer chemotherapy drug
102
How do intercalators work?
By inhibiting topoisomerase
103
What do intercalators generate?
Generate as stable ternary complex between the DNA, enzyme and drug – with the DNA strands cleaved, so causes strand cleavage – which is less well repaired by cancer cells
104
What are the types of topoisomerases and give examples of each
Type I topo – **Camptothecin**
Type II topo – **Etoposide** (and intercalators)
Topoisomerase II is over expressed in some resistance
105
Tell me the following about the topoisomerase II, **etopside**
1. Chemical nature
2. Mechanism of action
3. Cell cycle specificity
4. Toxicity
**1. CHEMICAL NATURE:** semi-synthetic alkaloid derived from podophyllotoxin
**2. ACTION:** Binds to tubulin but this is not believed to be important for the therapeutic effect. May stimulate topoisomerase II to cleave DNA
**3. CELL CYCLE SPECIFICITY:** Greatest lethality seen in S and G2 phases
**4. TOXICITY:** Leukopenia, nausea and vomiting more common with oral administration, alopecia
106
Tell me the following about the antibiotic **dactinomycin (actinomycin D, Cosmagen)**
1. Chemical nature
2. Mechanism of action
3. Resistance
4. Cell cycle specificity
5. Toxicity
**_DACTINOMYCIN (Actinomycin D, Cosmagen)_**
**1. CHEMICAL NATURE:** An antibiotic from a Streptomyces species. It contains two cyclic polypeptides which are linked by a chromophore moiety.
**2. MECHANISM OF ACTION:** Binds noncovalently to DNA. Intercalates between adjacent GC base pairs. It inhibits RNA polymerase more than DNA polymerase
**3. RESISTANCE:** Decreased ability of cells to take up or retain the drug.
**4. CELL CYCLE SPECIFICITY:** Cell cycle stage-nonspecific
**5. TOXICITY:** Nausea and vomiting, local vesicant, myelosuppression, redness of skin where radiation has been given, alopecia
107
Tell me the following about **Daunorubicin (duanomycin, rubidomycin)**
1. chemical nature
2. mechanism of action
3. resistance
4. cell cycle specificity
5. toxicity
**_DAUNORUBICIN (Daunomycin, Rubidomycin)_**
**1. CHEMICAL NATURE:** An anthracycline glycoside isolated from a Streptomyces species, red color
**2. MECHANISM OF ACTION:** Intercalates between base pairs of DNA and inhibits RNA synthesis
**3. RESISTANCE**: Decreased uptake or more rapid removal of the drug
**4. CELL CYCLE SPECIFICITY**: Cell cycle stage-nonspecific
**5. TOXICITY:** Nausea and vomiting, Myelosuppression, Cardiomyopathy, Alopecia
108
Tell me the following about **doxotubicin (adriamycin)**
1. Chemical nature
2. mechanism of action
3. resistance
4. cell cycle specificity
5. toxicity
6. therapeutic use
**_DOXORUBICIN (Adriamycin)_**
**1. CHEMICAL NATURE:** Same as Daunorubicin except there is an additional hydroxyl group
**2. MECHANISM OF ACTION:** As for Daunomycin
**3. RESISTANCE:** As for Daunomycin
**4. CELL CYCLE SPECIFICITY:** Cell cycle stage-nonspecific but greater efficacy in S
**5. TOXICITY:** Similar to daunomycin
**6. THERAPEUTIC USE:** Acute leukemias, lymphomas, many solid tumors including sarcomas
109
Tell me the following about **bleomycin (blenoxane)**
1. chemical nature
2. mechanism of action
3. resistance
4. cell cycle specificity
5. toxicity
**_BLEOMYCIN (Blenoxane)_**
**1. CHEMICAL NATURE:** Bleomycin sulfate is a mixture of 13 different bleomycin peptides derived from a Streptomyces species
**2. MECHANISM OF ACTION:** Inhibits DNA synthesis. Binds to DNA and causes DNA strand breaks
**3. RESISTANCE:** Increased hydrolase activity, decreased uptake and increased efflux
**4. CELL CYCLE SPECIFICITY:** Increased sensitivity in G2
**5. TOXICITY:** Fever, dermatologic reactions, pulmonary toxicity and fibrosis, minimal
110
Tell me about strand cleavage in bleomycin
111
What are the 6 types of resistance?
1. Decreased transport
2. Gene amplification
3. Increased DNA repair
4. Increase in deactivating enzymes
5. Modified enzymes
6. **Multiple drug resistance (MDR)**
7. P-glycoprotein (p170)
ATP dependent exporter
Broad spectrum of action – exports daunomycin, vinblastin, etoposide, taxol….
Overexpressed in resistant cells
112
Tell me about combination therapy and provide examples
Increase log kill, not toxicity, sub-additive host toxicity
Greater range of side effects, but less severe
e.g., Hodgkin’s lymphoma treated with a combination of:
Cisplatin, bleomycin, vincristine and daunomycin
113
Timeline depicting the historical milestones in the development of therapies for NSCLC
