Lecture 4 - chemotherapy drugs

Question 1

what are factors dependant on types of cancer treatment?

Answer 1

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

Question 2

how does chemotherapy work?

Answer 2

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).

Question 3

what are problems with chemotherapy ?

Answer 3

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

Question 4

what are types of cancer drugs?

Answer 4

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.

Question 5

describe alkylating agents

Answer 5

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

Question 6

what are consequences of alkylation by alkylating agents?

Answer 6

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.

Question 7

What are groups of alkylating agents?

Answer 7

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)

Question 8

what are clinically used mustards?

Answer 8

Carmustine
Gliadel wafers

Question 9

describe platinum based drugs

Answer 9

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

Question 10

what are cOnswqunes of cisplatin binding to ]DNA?

Answer 10

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

Question 11

what are ciplatin side effects?

Answer 11

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

Question 12

describe carboplatin

Answer 12

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).

Question 13

what are new anti caner drugs?

Answer 13

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

Question 14

describe anthacyclien based drugs

Answer 14

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.

Question 15

what is the mode of action of doxorubicin?

Answer 15

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

Question 16

what are side ffecst of anthracyclines?

Answer 16

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).

Question 17

describe Actinomycin D Mechanism of action

Answer 17

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

Question 18

Describe spindle poisons

Answer 18

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

Question 19

explain the mechanism for action of single poisons

Answer 19

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

Question 20

what are other examples do spindle poisons ?

Answer 20

vincristine for Acute leukaemia’sHodgkin’s lymphomanon-Hodgkin’s lymphomaSmall cell lung cancer. Adverse effects: Peripheral neuropathy

rosy periwinkle stops formation of microtubules

Question 21

explain the sue of taxol and taxoteres

Answer 21

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

Question 22

how do antimetabolites work ?

Answer 22

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

Question 23

what is needed to duplicate DNA

Answer 23

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

Question 24

describe the process of nucleotide synthesis

Answer 24

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

Question 25

how do purine analogues work?

Answer 25

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

Question 26

what re pyrimidine analogues?

Answer 26

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

Question 27

how does inhibition of pyrimidine synthesis by 5-fluoruruccel work

Answer 27

5FU is converted to 5-dUMP which competes
with deoxymonophosphate for the enzyme
Thymidylate synthase- required for DNA synthesis

Question 28

methotrexate

Answer 28

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

Question 29

top1

Answer 29

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

Question 30

topotecan

Answer 30

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