Lecture 4 - chemotherapy drugs Flashcards
what are factors dependant on types of cancer treatment?
course of treatment deeds on type of cancer, progress of the disease, available treatment options , health of the patient and patients choice.
surgery and radiation for tumours theatre not spread
chemotherapy for spread tumours
how does chemotherapy work?
Chemotherapy is the treatment of cancer with one or more cytotoxic drugs
Chemotherapy may be given with a intent for cure or it may aim to prolong life or to improve symptoms. Often used in conjunction with other cancer treatments, such as radiation therapy or surgery.
Chemotherapy is good for metastasised cancer as it is a systemic therapy
Traditional chemotherapeutic agents act by killing cells that divide rapidly. this means chemotherapy also kills normal cells that divide rapidly: cells in the bone marrow, digestive tract, and hair follicles
most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).
what are problems with chemotherapy ?
Treatments are non-specific, attack healthy cells as well as normal cells.
Cancers are heterogeneous- not all cells same- genes mutated so
Bits of some cancers or metastases may be resistant to some drugs
Cancers can develop resistance to chemotherapy (for example with platinum-drugs):
Decreased drug uptake/increased efflux
Enhanced tolerance of DNA adducts
Enhanced repair of DNA adducts
Increased drug deactivation by intracellular glutathione
Toxicity to normal cells
what are types of cancer drugs?
Platinates
Anthracyclines
Taxanes
Alkylators
Antimetabolites
Topoisomerase inhibitors
These drugs all act by inducing cellular apoptosis
Drugs target all rapidly dividing cells including bone marrow, hair cells, foetuses.
Pregnancy and breast feeding are contraindictions to chemotherapy for most drugs.
describe alkylating agents
Alkylation - transfer of an alkyl group from one molecule to another- In medicine,
alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells
Alkylation is accomplished with the class of drugs called alkylating agents- attaches an alkyl group (CnH2n+1) to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring
what are consequences of alkylation by alkylating agents?
DNA fragmented by repair enzymes in their attempts to replace the alkylated bases
Addition of the alkyl group to the base causes the mispairing of the nucleotides leading to mutations
alkylating agents cause formation of cross-bridges, bonds between atoms in the DNA- two bases are linked together by an alkylating agent that has two DNA binding sites. Cross-linking prevents DNA from being separated for synthesis or transcription. As this is necessary in DNA replication, the cells can no longer divide.
What are groups of alkylating agents?
nitrogen mustards; ethylenimes; alkylsulfonates; triazenes; piperazines; and nitrosureas.
eg nitrogen mustard: Target DNA. Prevents DNA replication and transcription.
Targets cells particularly at the junction of the dermis and epidermis (basal layer)
.
Usually given in cycles i.e. Cyclophosphamide (50-250 mg/m2 daily)
what are clinically used mustards?
Carmustine
Gliadel wafers
describe platinum based drugs
Used most commonly in treatment of, ovarian, testicular, lung, bladder, cervical and head and neck cancer
Platinum-based chemotherapeutic drugs (termed platinum analogues) act in a similar manner to alkylating agents.
These agents do not have an alkyl group, but nevertheless damage DNA.
They permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as “alkylating-like”.
Main ones to remember Cisplatin and Carboplatin
what are cOnswqunes of cisplatin binding to ]DNA?
CISPALSTIN BINDS TO DNA AND CAUSES A CRTICIAL STRCUTURE CHANGE IN THE DNA - BEND OF 45 DEGREES
replication inhibition, transcription inhibition, cell-cycle arrest
dna repair
cells eath
what are ciplatin side effects?
Small therapeutic window
Neurotoxic (nerve damage)-visual perceptions, hearing disorders-binds membrane-bound
Nephrotoxic (kidney damage)-related to reactive oxygen species- dose limiting
Causes nausea and vomiting- often given with prophylactic anti-emetics
Myelotoxicity: This agent can also cause profound bone marrow suppression
describe carboplatin
Delivers the same drug as cisplatin, but with the chloride ligands replaced with bidentate dicarboxylate.
Used to treat the same cancers as cisplatin (although preferred first line drug for ovarian cancer and small cell lung cancer) and is used particularly with patients who have poor tolerance of cisplatin. Marketed as less toxic but clinical trials show varying results
Dose: i.v. ~400 mg/m2 (cisplatin 50-120 mg/m2) over 15 to 60 min every 4 weeks. DLT is myelosuppression. Takes less time to administer than cisplatin
Sold as carboplatin and Paraplatin™ (Bristol Myers-Squibb) as prepared solutions (10 mg/mL).
what are new anti caner drugs?
Satraplatin will also be the first platinum anti-cancer drug that can be administered
orally instead of intravenously, allowingpatients to be treated at home.
Most platinums are usually given in combination with other drugs i.e. commonly
Oxaliplatin is typically administered with fluorouracil and folinic acid (leucovorin) in a
combination known as FOLFOX for the treatment of colorectal cancer
describe anthacyclien based drugs
Anthracycline based drugs – intercalating drugs
Natural products derived from various strains of Streptomyces bacteria.
Four-ring structure linked via glycosidic bond to daunosamine.
Doxorubicin = for many solid tumours.
what is the mode of action of doxorubicin?
Doxorubicin intercalates between base pairs and causes local unwinding of DAN as the base pairs separate.
The hydrophobic faces of the DNA base pairs interact with the planar rings of doxorubicin
intercalation causes DNA breaks and interferes with the action of topoisomerase II. this causes accumulation of DNA breaks. there is no RNA and protein transcribed. topoisomerase II is an enzyme which breaks and reconnects DNA strands.
Doxorubicin (epirubicin) iv injection every 21 days 60-75 mg/m2
what are side ffecst of anthracyclines?
Nausea and vomiting, extravasation can cause tissue necrosis, bone marrow depression/ immunosupression, myelosuppression, infertility, dehydration.
Myocardial toxicity from cumulative doses of around 450-500mg/m2. Patients need cardiac monitoring (ECG). ( patients should have cardiac function assessed before use).
describe Actinomycin D Mechanism of action
actinomycin binds to the DNA transcription initiation complex and blocks RNA polymerase from making RNA chain. this leads to inhibition of transcription.
used mainly in paediatric caner as IV.
has same SE as doxorubicin but no cardio toxicity
Describe spindle poisons
spindle poison target the microtubules.
microtubules are essential for cell movement, cell shape, movement of cargo within the cell and mitosis
vinca alkaloids and taxanes are examples
explain the mechanism for action of single poisons
the mehcnasoms of action involves binding tubules to monomers and keeping microtubules from forming
work in a cell specific manner halting affected cells from mitosis and causing cells death
vinca alkaloid administered as IV and after injection metabolised by liver and eventually excreted
what are other examples do spindle poisons ?
vincristine for Acute leukaemia’sHodgkin’s lymphomanon-Hodgkin’s lymphomaSmall cell lung cancer. Adverse effects: Peripheral neuropathy
rosy periwinkle stops formation of microtubules
explain the sue of taxol and taxoteres
used to treat ovarian, breast, advanced non small lung cancer, gastric adenocarcinomas, aids related sarcomas, breast, head and neck cancer
paclitaxel 175mg/m2 over 3 hrs every 3 weeks
docetaxel 75-100mg/m2 once every 3 weeks
side effects include nausea, vomiting, DLT is neutropenia and secondary infections are common
paclitaxel shortens microtubules and so interferes with the normal breakdown of microtubules during cell division. used in combination with doxetaxel forms the drug category taxanes
how do antimetabolites work ?
may work one of 2 ways
antimetabolites may be incorporated instead of the normal metabolite - antimicrobial acts as competitive substate
antimetabolites may inhibit the enzymes that are used in the synthesis of uptake of metabolites - antimetabolites act as enzyme inhibitors
both methods induce cellular apoptosis
many nucleic acid analogues may also be incorporated into DNA
what is needed to duplicate DNA
to divide cells need to duplicate DNA in chromosomes thus need a source of nucleotides - purines and pyrimidines
purines are guanine and adenine
pyrimidine are guanine, thymine and uracil
describe the process of nucleotide synthesis
purines and pyrimidines are the basic building molecules of DNA.
purines and pyrimidines can be synthesised in 2 ways:
de novo pathway - this s when the purines and pyrimidines bases made are new especially to make DNA
salvage pathway: this is when purines are pyrimidines bases are reused from the destruction of old DNA
in normal cells, the de novo pathway is inactive and salvage pathway is active
in cancer cells de novo pathway is active and salvage pathway is inactive
inhibition of the de novo pathway can allow the drug to target cancer cells - normal cells use the salvage pathway
how do purine analogues work?
purine analogues such as 6-thioguanine and 6-mercaptopurine work by inhibiting the synthesis of purine. they prevent the synthesis of guanine monophosphate (GMP_
dan can’t be replicated and cells can’t divide
mercaptopurine dose is 50-75mg/m2 per day
side effects are nephrotoxicity, vomiting, myelo-suppresion
used in leukemias and may cause liver toxicity
what re pyrimidine analogues?
gemcitibine is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis. It blocks the progression of G1/S phase through the cell cycle.
when gemcitibine is incorporated into the DNA, it prevents ncuelotiides from being added to DNA chain, and os there is cell apoptosis
also inhibits ribonucleotide reductase so ribonucelotides cannot be converted to deoxyribonucletides and there is decrease in deoxyribonucelootide concentrations
demcitibine is used in bladder, pancreatic and breast cancer
how does inhibition of pyrimidine synthesis by 5-fluoruruccel work
5FU is converted to 5-dUMP which competes
with deoxymonophosphate for the enzyme
Thymidylate synthase- required for DNA synthesis
methotrexate
Cancer cells need folic acid to survive
Methotrexate binds to DHFR instead of Folic acid- cells cant make any new thymidine bases
Interferes with DNA sysnthesis, transcription etc – cell cant divide
top1
TOP1relaxes supercoiled DNA to remove helical constraints that can otherwise hinder DNA replication and
transcription and thus block cell growth
Topoisomerase 1 inhibitorsblock the ligation step of the cell cycle, which generates DNA single which leads to more lethal double-strand breaks
Converts easy to repair SS breaks to hard to repair DS breaks
The cell recognises that the DNA is broken
Badly- as it has DS breaks leading to apoptotic cell death.
Topoisomerase I inhibitors include irinotecan, topotecan, and camptothecin, andtopoisomerase IIinhibitors
include etoposide, doxorubicin, and epirubicin
topotecan
Topotecan is a topoisomerase 1 inhibitor
Topotecan binds to the topoisomerase DNA complex and once a single strand nick has been made to relieve tortional stress in the DNA it prevents this re-ligating resulting in Double strand breaks
Use ovarian cancer, small cell lung cancer
Topotecan is a really potent radiosensitiser and chemosensitiser
BECAUSE- radiotherapy and chemotherapy cause single strand breaks which can often be repaired by cancer cells
- Topotecan converts these single strand breask caused by these drugs to
become double strand breaks which are very hard for the cancer cell to
repair
