Chemotherapy L5 Flashcards
4 characteristics of cancer cells?
- have an abnormally high mitotic rate.
- show signs of de-differentiation and assume features of immature cells.
- can grow in the absence of mitogens.
- are immortal.
Two classes of anticancer drugs are used clinically:
what are they?
cytotoxic (antineoplastic) drugs – Part 1
molecular targeted drugs – Part 2
Cytotoxic anticancer drugs target DNA replication by:
(5)
- alkylation and/or cross-linking (covalent)
- intercalation (non-covalent)
- acting as antimetabolite
- inhibiting topoisomerase enzymes
- inhibiting mitotic spindle dynamics
give some Anticancer agents that bind covalently to DNA
nitrogen mustards: melphalan, cyclophosphamide,
nitrosoureas: lomustine
aziridines: mitomycin C
and platinum compounds: cisplatin
are nitrogen mustards very reactive?
yes
what about nitrogen mustards makes them so reactive
2 chloroethyl groups - unstable
wihch forms the imonium io at alkaline / neutral pH
forms the carbonium ion (electrophile)
binds to electrons on O6 / N7 in guanine DNA
each chloroethyl group binds a guanine - linking them
the use of nitrogen mustards leads to ______ are formed beween or within DNA strands
Crosslinks are formed beween or within DNA strands
as well as cross links forming, nitrogen mustards can cause what?
If second reaction occurs with water instead of guanine, monoalkylated guanine can result
in GC to AT transition
describe the selectivity of nitrogen mustards?
not very selective.
Reactioncan also occur with other nucleophilic groups in RNA and protein (cause of general toxicity)
____________ is the most-commonly-used nitrogen mustard
Cyclophosphamide is the most-commonly-used nitrogen mustard
Cyclophosphamide is used against?
(against lymphoid tumours and carcinomas in breast, lung, ovary)
is Cyclophosphamide a pro drug?
Cyclophosphamide needs to be metabolised in the liver by cytochrome P450 system to become activated to a phosphoramide mustard
Nitrogen mustards usually (do/do not) accumulate in a particular tissue?
usually do not
there is an exception though:
Melphalan is an exception. As phenylalanine is a precursor of melanin, melphalan accumulates in melanomas (pigmented skin tumours of melanocytes)
Cyclophosphamide and melphalan are usually administered ?
Cyclophosphamide and melphalan are usually administered orally
nitrosureas have both….. actions?
both alkylating and carbamoylating agents
they react with a variety of groups to attach an alkyl (R-CH2-) or a carbamoyl (R-N-CO-) moiety
can all nitrosureas produce interstrand cross-links in duplex DNA in which N7 and O6 positions in guanine are preferred sites of attack?
yes.
do you know what base splitting is for nitrosureas?
the nitrosureas splits to form:
and isocyanate and a carbionium ion
give 2 examples of nitrosureas?
Carmustine and Lomustine
advantages of carmustine and lomustine over nitrogen mustards?
why is this important in their clinical use/
More lipophilic than nitrogen mustards
enables excellent brain penetration, and they therefore remain important in treatment of brain tumours
what limits the usefulness of carmustine and lomustine (nitrosureas)?
Reduction in white blood cells and platelets, as well as damage to various organs limits the usefulness of nitrosoureas
lomustine is administerd?
orally
60% bioavailability
how is carmustine administered?
IV
give the main anticancer drug containing platinum
cisplatin
only active in Cis form
how does cis platin act?
cross-linking agent in DNA
describe the mechanism of action for cis platin
principal sites of reaction at physiological pH are the N7 atoms of guanine and adenine
forms an intrastrand cross link between 2 adjacent Guanine nucleotides
bends the DNA strand - causes changes in the major groove
cis platins cross links:65% of adducts represented intrastrand cross-links on pGpG, 22% on pApG (but not pGpA) sequences, and 13% a mixture of other adducts (including interstrand cross-links at less than ___%).
65% of adducts represented intrastrand cross-links on pGpG, 22% on pApG (but not pGpA) sequences, and 13% a mixture of other adducts (including interstrand cross-links at less than 5%.
Cisplatin greatly improved the treatment of ____ _______and moved cure rates from 5-15% to 70-90% for metastatic stages of the disease.
Cisplatin greatly improved the treatment of testicular cancer and moved cure rates from 5-15% to 70-90% for metastatic stages of the disease.
how is cisplatin administerd?
Cannot be used orally (no bioavailability); administered I.V.
what reactrions in the cell inactivate cisplatin?
Is inactivated by reaction with SH groups in glutathione and (cysteine-rich) metallothioneins.
(it reacts with thiol groups)
adverse effects of cisplatin?
Major adverse effect is renal toxicity as observed with heavy metals.
Also, bone marrow suppression is dose-limiting.
carboplatn vs cisplatin?
Carboplatin (and oxaliplatin) more favorable toxicity profile
how are Aziridines used as anticancer drugs?
key exmaple?
antibacterial drug - causes DNA alkylation and DNA cross linking
key exmaple: mitomycin C - produced by bacteria.
is Mitomycin C used as an antibacterial?
no - anticancer
. Interestingly, mitomycin C has ___ effect on purified DNA in vitro?
. Interestingly, mitomycin C has no effect on purified DNA in vitro unless a cell extract is added
how does P53 play into DNA damage?
If DNA damage caused by alkylation and crosslinking is beyond repair, p53 protein will trigger apoptosis
p53 protein is a ….
p53 protein is a tumour suppressor
Drugs that bind noncovalently with DNA to prevent effective DNA replication and gene expression include
Drugs that bind noncovalently with DNA to prevent effective DNA replication and gene expression include anthracyclines (doxorubicin, daunorubicin), and actinomycins (actinomycin D).
as well as planar integration into unwound DNA, Anthracyclines also damage DNa how?
Anthracyclins also induce oxidative damage to DNA, which results in DNA fragmentation (like bleomycin)
free radicals attack DNA
which anthrocyclins lack the capacity to generate free radicals?
Anthracycline analogues with a modified structure, such as mitoxantrone , lack this property of quinone-type free radical generation.
anthracyclins have bad side effects in which organs
lung and cardiac tissue
Mitoxantrone is used in treatment of ….
Mitoxantrone is used in treatment of breast cancer, acute myeloid leukemia, and certain lymphomas
mechanism for how anthracyclins generate free radicals?
Antimetabolites interfere with the production of DNA and RNA by one or both of two major mechanisms:
what are they?
Antimetabolites interfere with the production of DNA and RNA by one or both of two major mechanisms:
(i) inhibition of normal precursor production, and
(ii) substitution of purines and pyrimidines in nucleic acid synthesis.
what does methotrexate inhibit?
folic acid synthesis
which enzyme does methotrexate inhibit?
The antifolate action of methotrexate includes inhibition of the enzyme dihyrofolate reductase (DHFR)
which antibiotic is methotrexate analogus to?
trimethoprim
methotrexate competes with what for uptake into mamallian cells?
folic acid - therefore its actively transported into mamallian cells
Intense use of methotrexate is often associated with what?
toxicity to normal tissues
its very toxic
inthe clinical use of methyltrexate - whats usually given along side it and why?
methyltrexate is often given along side leucovorin.
Leucovorin given in small doses provides an alternative pathway for cells to synthesize tetrahydrofolate (needed for DNA synthesis (through dTMP))
this allows normal cells to produce just enough tetrahydrofolate for their own health - while severely restricting the amount the cancer can produce.
methotrexate and leucovorin
____is often used together with leucovorin:
5-fluorouracil is often used together with leucovorin:
describe actions of 5-fluorouracil
5-fluorouracil is converted in the cell into 5-fluoro-2’-deoxyuridine (analogue of dUMP), which inhibits TS, especially in the presence of methylene tetrahydrofolate; the latter is produced from leucovorin
describe the actions of 6-mercaptopurine and 6-thioguanine
The purine antagonists 6-mercaptopurine and 6-thioguanine are analogues of hypoxanthine and guanine, respectively.
Analogous to 5-fluorouracil, these thiopurines cause nucleotide synthesis inhibition as well as being incorporated into nucleic acids (after their activation to triphosphate nucleotides).
what do type I topoisomerases do?
singel strand breaks - so release single strand super coiling
what do type 2 topoisomerases od?
double strand brakes
type I topoisomerases include: ….
type I: camptothecins (from bark of the tree Camptotheca acuminate) and topotecan
type II topoisomerases include…..
type II: etoposides, anthracyclines, mitoxantrone and epipodophyllotoxins
describe how intervention with spindle formation can be anticancerous
Vinca alkaloids (vinblastine and vincristine) bind to tubulin dimers, leading to disassembly of microtubules (association inhibited)
Taxol (paclitaxel - brand name) bind to microtubules, and thereby stabilize these structures (dissociation inhibited)
how does taxol work?
binds to microtubules -stabilsing the structure - inihibts dissociation.
how do Vinca alkaloids work on cancer?
Vinca alkaloids (vinblastine and vincristine) bind to tubulin dimers, leading to disassembly of microtubules (association inhibited)
In summary, cytotoxic anticancer drugs can target DNA by:
(5)
- alkylation and/or cross-linking (covalent)
- intercalation (non-covalent)
- acting as antimetabolite
- inhibiting topoisomerase enzymes
- inhibiting mitotic spindle dynamics
why might targeting rapidly proliferating cells not be effective in cancer?
Cells at centre of solid tumours grow very slowly, and are often less responsive to drug treatment
- sarcomas (connective tissue, e.g. muscle or bone),
- carcinomas (arising from epithelial cells, e.g. breast, colon),
- lymphomas (lymph nodes or lymphoid tissue)
describe the toxic effecst of drugs targeting DNA replication and synthesis?
Severe toxicity:
• hair loss
• depression of gametogenesis: sterility • bone marrow suppression
• nausea and vomiting
• gastrointestinal disturbances
t or F
Many breast cancers grow more rapidly in the presence of female steroid hormones.
T
describe Tamoxifen
anti-oestrogen that competitively binds to the estrogen receptor, but with a lower affinity than estrogen - acts as antagonist
successfully used against 70% of breast cancers (ER and PR positive), and inhibits cell proliferation
problems with tamoxifen?
However, tamoxifen can exert estrogen agonist effects in other tissues such as bone and uterus
whats Toremifene an improement on?
Toremifene is a tamoxifen analogue without estrogen agonist properties.
what does aromatase do?
Aromatase is the enzyme in the estrogen biosynthetic pathway that converts androgen precursors to estradiol
describe anastrozole - how does it work?
Postmenopausal women have high circulating estrogen levels which is mainly due to estrogen synthesis in fat and muscle (opposed to estrogen synthesis in the ovary in pre-menopausal women). Anastrazole inhibits the aromatase enzyme that mediates a final step in this estrogen synthesis pathway.
anastrozole use in which people?
post menopausal people
2 drugs used to treat prostate cancer?
Flutamine
goserelin
how does Flutamide work?
Flutamide is an anti-androgen drug that competes with testosterone for binding to the androgen receptor, and inhibits cell proliferation
describe goserelin
Goserelin (goseralin) is a synthetic decapeptide homologue of gonadotropin-releasing hormone (GnRH) that acts as a strong agonist on the GnRH receptor.
GnRH indirectly stimulates testosterone synthesis in testis (via stimulation of luteinising hormone), but sustained agonist binding at the GnRH receptor results in complete inhibition of testosterone synthesis
with some cancers, hormones can directly inhibit growth - give an exmaple
Glucocorticoids are steroid hormones that up-regulate (via binding to glucocorticoid receptor) the expression of anti-inflammatory proteins and repress growth of lymphocytes.
Prednisone is a prodrug that is converted in liver into prednisolone.
It is used against acute lymphoblastic leukemia.
is Prednisone a pro drug?
yes
converted to prednisolone by hte liver
are some monoclonal antibodies anti cancer drugs?
yess
Rituximab
used to treat?
Rituximab is a humanised monoclonal antibody against CD20, a protein present on the surface of many transformed B-cells (lymphocytes) in Hodgkin’s disease and non-Hodgkin’s lymphoma.
how does Rituximab wokr?
Although its exact mechanism is not yet clarified, rituximab can lyse CD20 cells in vitro through antibody-dependent cell-mediated cytotoxicity, activation of the complement cascade, and introduction of apoptosis.
Rituximab was the first monoclonal antibody approved for therapeutic use against cancers, either alone or in combination with classical chemotherapy.
describe Trastuzumab
Trastuzumab (sold as Herceptin) is a humanised monoclonal antibody against the human epidermal growth factor receptor 2 (HER2)
how does Trastuzumab wokr?
Trastuzumab binds to extracellular domain of human epidermal growth factor receptor 2 (HER2) and prevents binding of epidermal growth factor. HER2 is overexpressed in 25 – 30% of breast cancers
how is trastuzumab administered?
Trastuzumab is administered intravenously, once weekly, either alone or in combination with classical anticancer agents for metastatic breast cancer that overexpress HER2.
side effecst of trastuzumab?
Common side effects include chills, asthenia, fever, and nausea.
Rarely, trastuzumab can cause cardiac dysfunction.
However, the risk of cardiac dysfunction increases significantly if trastuzumab is given together with other cardiotoxic agents such as anthracyclines.
describe Bevacizumab
Bevacizumab is a humanised monoclonal antibody that binds to and inhibits the human vascular endothelial growth factor (VEGF).
how does Bevacizumab work?
Bevacizumab is a humanised monoclonal antibody that binds to and inhibits the human vascular endothelial growth factor (VEGF).
VEGF is a soluble protein that plays an important role in inducing blood vessel formation, thereby allowing tumours to grow beyond a few millimetres in size.
inhibits tumour angiogenesis
Bevacizumab is administered in combination with _____________for the treatment of metastatic colorectal cancer.
Bevacizumab is administered in combination with 5-fluoro-uracil for the treatment of metastatic colorectal cancer.
Studies indicate that bevacizumab is also active in advanced ….
Studies indicate that bevacizumab is also active in advanced non-small cell lung cancer (NSCLC) and breast cancer.
side effecst and problems with bevacizumab
Due to its anti-angiogenic action, bevacizumab can interfere with wound healing and increase the risk of bleeding or gastrointestinal perforation.
Other side effects include hypertension and proteinuria.
how does Cetuximab work?
- EFGR usually binds EFG, dimerises and increases tyrosine kinase activity after autophosphorylartion
- cetuximab prevetns EFGR binding
- by inhibiting EGFR-associated tyrosine kinases.
cetuximab is used against?
Used against colorectal cancer and head and neck cancer
how does Gefitinib work?
Gefitinib inhibits the activity of the activated EGF receptor by blocking its ability to dimerise and function as a tyrosine kinase.
describe Cetuximab
Cetuximab is a human/mouse chimeric monoclonal antibody that binds to the extracellular domain of EGFR
• “-tinib” =… what sort of drug?
• “-tinib” = tyrosine kinase inhibitor
describe the Use of small molecule inhibitors for Chronic Myeloid Leukemia
Imatinib inhibits Bcr-Abl
describe how Imatinib works?
- Imatinib inhibits Bcr-Abl
- Imatinib also inhibits c-kit, a growth factor-dependent tyrosine-kinase-receptor in mast cells, which is overexpressed in gastrointestinal stromal tumours (soft tissue carcinoma)
Masivet used to target mutated c-kit in dogs for treatment of inoperable grade II-III mast cell tumours
Erlotinib and gefitinib are orally active, potent, and selective quinazoline derivatives that inhibit ….
Erlotinib and gefitinib are orally active, potent, and selective quinazoline derivatives that inhibit EGFR tyrosine kinases
toxicity of Erlotinib and gefitinib
Toxicity is mainly skin rashes and diarrhea.
whasta. philodelphia chromosome?
Most patients with Chronic Myeloid Leukaemia (CML) carry the Philadelphia chromosome, which results from a reciprocal exchange of genetic material between the long arms of chromosomes 9 and 22.
long Cr 9
short Cr 22
The BCR-ABL protein has_____ ____activity and is constitutively active
The BCR-ABL protein has tyrosine kinase activity and is constitutively active
Erlotinib inhibits EGFR tyrosine kinase and is use din?
Erlotinib inhibits EGFR tyrosine kinase (lung cancer)
infor about Toceranib (Palladia, Pfizer) and mastinib (Masivet, AB Science):
Tyrosine kinase inhibitors are also used in veterinary medicine. Toceranib (Palladia, Pfizer) and mastinib (Masivet, AB Science) are used in the treatment of non-resectable grade II – III mast cell tumours (mastocytomas) in connective tissue in dogs. Grade II cells are intermediately differentiated with a potential for locally invasive metastasis. Grade III cells are poorly differentiated or undifferentiated with a high potential for metastasis. Both drugs are also used for c-kit mutations (see above).
how are anticancer drugs selective (3)
differential accumulation:
differential activation:
differential importance:
how are anticancer drugs selecltive through different accumulations?
some tumour cells have enhanced rates of glycolysis, and as a result, reduced pHin. Drugs (e.g., anthracyclines) that are trapped in the cell through protonation (thus becoming cationic) are accumulated more in tumour cells than in normal cells.
how are anticancer drugs selective through differential activation
drugs that are activated by reduction (e.g. alkylating agent Mitomycin C), have enhanced toxicity in hypoxic tumour cell in solid tumours.
howa re anticancer drugs selective based on differential importance:
Alkylating and cross-linking agents, antimicrotubule drugs and antifolates are effective because cancer cells have a high demand in DNA replication and cell division.
Antibodies and small molecule inhibitors target signaling pathways that are permanently switched on in cancer cells.
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