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4. 21 > Lecture 4: Cancer chemotherapy > Flashcards

Lecture 4: Cancer chemotherapy Flashcards

1
Q

What are the types of cancer treatment?

A
  • Surgery – non spread tumour
  • Radiation – non spread tumour
  • Chemotherapy – spread tumour
  • Biological therapies (cell therapy, immuno-modulators)
  • Targeted therapy
  • Gene therapy
  • Natural products
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2
Q

How does chemotherapy work?

A

Chemotherapy is the treatment of cancer with one or more cytotoxic drugs as part of a standardised regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms. It is often used in conjunction with other cancer treatments, such as radiation therapy or surgery. Chemotherapy Is good for metastases cancer as it is a systemic (spreads through the body) therapy. Traditional chemotherapeutic agents act by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that chemotherapy also harms cells that divide rapidly under normal circumstances, cells in the bone marrow, digestive tract and hair follicles. This result in the most common side effect of myelosuppression (decreased production of blood cells), hence also immunosuppression, mucositis (inflammation of the lining if the digestive tract), and alopecia (hair loss)

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3
Q

What are the problems with chemotherapy?

A
  • Treatments are non specific – attack healthy cells too
  • Cancers are heterogeneous – not all the cells are the same
  • Cancers can develop resistance (for example with platinum drugs)
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4
Q

What are the 5 major classes of chemotherapy agents?

A
  • Platinates
  • Anthracyclines
  • Taxanes
  • Alkylators
  • Antimetabolites

These drugs all act by inducing cellular apoptosis. The drugs target all rapidly dividing cells including bone marrow, hair cells, foetuses.

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5
Q

What is the site of action of cytotoxic agents at cellular levels?

A
  • antimetabolites: DNA synthesis
  • Alkylating agents: DNA
  • Intercalating agents: DNA transcription and DNa duplication
  • Spindle poisoms: Mitosis
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6
Q

What is alkylation and how do alkylating agents work?

A

Alkylation is the 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 to the guanine base of DNA at the #7 nitrogen atom of the purine ring.

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7
Q

What are the consequences of alkylating agents?

A
  • DNA fragmented by repair enzymes and their attempts to replace the alkylating bases
  • Addition of the alkyl group to the base causes the miss pairing of the nucleotides leading to mutations
  • Alkylating agents cause formation of cross bridges - bonds between atoms and the DNA. Two bases are linked together by an alkylating agent that has two DNA binding size. This cross linking prevents DNA from being separated for synthesis for transcription as this is necessary in DNA replication, so the cells can no longer divide
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8
Q

What are the groups of alkylating agents?

A
  • Nitrogen mustards
  • Ethylenimes
  • Alkylsulfonates
  • Piperazines
  • Nitrosureas
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9
Q

How do mustards work?

A

Target DNA. Prevents DNA replication and transcription. Targets cells particularly at the tight junctions of the dermis and epidermis (basal layer). Carmustine used to treat brain cancers made by Bristol-Myers squibb. Melphalan also called L-phenylalanine mustard or L-PAM. Used to treat a variety of cancers including myeloma, ovarian, lymphomas, leukaemia, brain cancers (glioma, glioblastoma, medulloblastoma), breast, small cell lung cancer, sarcomas, and melanoma.

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10
Q

Give examples of mustards

A
  • Cyclosphosphamide (50-250mg/m daily)
  • Melphalan (0.15-6 mg/kg daily for 5 days, every 4-5 weeks)
  • Carmustine (200mg once every six weeks)
  • Chlorambucil (0.2 mg/kg/day for 4-8 weeks)
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11
Q

What are the contraindications and side effects of mustards?

A

Contraindications are pregnancy and breast feeding. Side effects are nausea/ vomiting, myelosuppression, tissue damage, burning sensation in the injection site

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12
Q

What are the uses for nitrogen mustard?

A
  • Hodgekins disease
  • Non hodhekins lymphoma
  • Breast
  • Ovarian
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13
Q

what causes resistance to alkylating agents?

A
  • Membrane transport may be decreased
  • The drug may be bound by gluthione via GSH-S-transferase or metallothiones in the cytoplasm and inactivated
  • The drug may be metabolised to inactive species
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14
Q

What are platinum based drugs most commonly used for?

A

treatment of ovarian, testicular, lung, bladder, cervical and head and neck cancer.

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15
Q

How do platinum based drugs work?

A

Platinum based chemotherapeutic drugs termed platinum analogues act in a similar manner to alkylating agents these agents don’t have an alkyl group but nevertheless still damage DNA. They bind to DNA and interfere with DNA repair

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16
Q

Give names of platinum based drugs and what they are used for

A
  • Cisplatin
  • Carboplatin (ovarian and small lung cancer)
  • Oxaliplatin (Colon cancer)
  • Nedaplatin
  • Heptaplatin (gastrin cancer)
  • Lobaplatin (Testicular cancer)
  • Satraplatin (Prostate cancer)
  • Picoplatin (Solid tumours)
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17
Q

What is the effect of cisplatin binding to DNA?

A

Cisplatin goes into the cells and binds to the DNA. The reactive chloride atoms directly link on to the bases in the DNA, causing the zip to be blocked so the DNA cant unwind and DNA replication cant take place. It happens again at the N7 position of the G base. This causes inhibition of replication, inhibition of transcription, cell cycle arrest, DNA repair cant happen and this al leads to cell death. When cisplatin binds to DNA this causes a critical structural change in the DNA – it causes a bend of 45 degrees, which means the protein wont have the same structure so DNA cant be replicated

18
Q

What are the mechanism of drug resistance of cisplatin?

A
  • Inactivating the drug by glutathione or metallothionein or other sulfer containing molecules
  • Increased repair of cisplatin aducts
  • Reduced cisplatin accumulation by changing the profile of uptake/efflux
  • Increased cisplatin adducts tolerance and failure of apoptotic pathway
19
Q

What are the side effects of cisplatin?

A
  • Very small therapeutic window
  • Neurotoxic effects such as visual perceptions, hearing disorder
  • Nephrotoxic - kidney damage related to the fact cisplatin causes reaction oxygen species. If this happens, treatment needs to be stopped
  • Causes nausea and vomitting so prophylactic anti emetics are given
  • Myelotoxicity - profound bone marrow suppression, this means the patient is suceptible to getting other infections
20
Q

What is the dose limiting factor of cisplatin?

A

It is nephrotoxic

21
Q

How does chemotherapy cause nausea and vomiting?

A

Chemotherapy causes nausea and vomiting because the body recognizes the dug as a foreign substance, this triggers the bodies nausea reflex to eject the foreign substance

22
Q

What is carboplatin?

A

It is a derivitive drug of cisplatin. It delivers the same drug as cisplatin but with the chloride ligands replaced with bidentate dicarboxylate. It is used to treat the same cancers in cisplatin although preferred first line drug for ovarian cancer and small cell lung cancer and it is used particularly with patients who have poor tolerability of cisplatin. It is marketed as less toxic than cisplatin. It is given through IV 400mg/m over 15 to 60 minutes every four weeks. It takes less time to administer carboplatin than cisplatin. It is sold as carboplatin and paraplatin as prepared solutions

23
Q

What are the mechanisms to overcome resistance of platinums?

A
  • Most platinum’s are usually given in combination with other drugs ie oxaliplatin is typically administered with fluorouracil and folinic acid – combination known as FOLFOX for the treatment of colorectal cancer.
  • Liposomes can be used – the drug is put into a little ball of fat. Liposomes can be targeted to a tumour, so there is less drug floating around the body. Polymers are also used to target tumours. Im some cases where the tumour has come out and spred. The drug is infused, not having the drug in the blood limits toxicity.
  • Platinum resistance modulators: adding drugs and modulators which modulate detoxifying enzymes that break up the drug
  • Combination of platinum drugs with molecularly targeted agents – bevacizumab, trasruzumab
  • Novel platinum drugs targeting resistance mechanisms – oxaliplatin, satraplatin. Satraplatin will be the first platinum anti cancer drug that can be administered orally instead of intravenously allowing patients to be treated at home.
24
Q

What are anthracycline based drugs - intercalating drugs?

A

These drugs are usually natural products derived from various strains of streptomyces bacteria. Discovered in screening programmed that tested antibiotics for cytotoxic activity. They have a four ring structure linked via glycosidic bonds to duanosamine. They have a flat structure which allows them to fit in between bases in DNA double helix. Eg doxarubisin, used for solid tumours and Duanorubicin, used for leukemia.

25
Q

What is doxorubicin mode of action?

A

Doxorubicin is an intercalating agent. It fits into the double helix and causes local unwinding of the helical structure as base pairs move apart. The hydrophobic faces of the DNA base pairs interact with the planer rings of doxorubicin. This intercalation causes DNA breaks as it intereferes with the action of topoisomerase II in breaking and reconnecting DNA strands. Resistance mechanisms are the efflux pumps and denaturing antibodies that can breakdown the drug

26
Q

What are the most effective anti cancer treatments?

A

Anthracyclines

27
Q

Name anthracyclines, their dose, administartion and indication?

A
  • Doxorubicin is given via IV injection every 21 days, 60 to 75mg. It is used for leukaemia, neuroblastoma, soft tissue and bone sarcoma, breast, ovarian, transitional bladder, thyroid, gastric, lymphoma, Bronogenic carcinoma and hodgkin’s disease
  • Daunorubicin – HIV related Kaposis sarcoma, 25-60mg/m
  • Epirubicin – IV every 3-4 weeks, 60-90mg/m. Used for breast, gastric, lung, colorectal, lhmphomas, leukaeias, multiple myeloma
28
Q

What are the side effects of anthracyclines?

A
  • Nausea and vomiting, extravasation can cause tissue necrosis, bone marrow depression/ immunosuppression, myelosuppression, infertility, dehydration
  • Myocardial toxicity from cumukative doses of around 450-500mg/m
  • 1-2 pateinets in every 100 develop acute myelogenous leukaemia syndrome. The risk is even higher for those concurrenkty treated with cyclopjoric radiotherapy
29
Q

What is actinomycin D, what is it used for, how is it administered, what are the side effects?

A

It is shown to have the ability to inhibit transcription it does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase. Its main use is in paediactri cancers where it is very effected. It is delivered IV. The side effects are the same as doxorubicin but no cardiotoxicity

30
Q

What are microtubules?

A

Microtubules are essential for cell shape, cell movement, movement of cargo within the cell, mitosis. Mitosis is essential for cell division – it’s the final stage where the cell splits. The microtubules grow and then shrink to pull the chromosomes into the 2 new cells.

31
Q

How do microtubules grow?

A

Microtubules grow by adding dimers – beta tubulin and alpha tubulin. All vinca alkaloids are administered IV. After injection, they are metabolized by the liver and excreted. Work in a cell cycle specific manner, halting mitosis of affected cells and causing cell death. The mechanism involves binding to tubulin monomers and keeping microtubules (spindle fibers) from forming.

32
Q

Give examples of spindle poisons, what it is used for, adverse effects, mechanism of action

A

Vinicristine - it comes from rosy periwinkle. It is used for acute leukaemia, hodgekins lymphoma, non hodgekins lymphoma and small cell lung cancer. Adverse effects are peripheral neauropathy - pain and tingling in nerves in your finger and toes. The mechanism of action is, the free tubulin dimers make the microtubule grow. Vinca bound tubulin dimer bind to the free tubulin dimers so that the microtubule can no longer be formed.

The drug taxol is one of the top selling anti canacer drug of all time. Taxol comes from the bark of pacific yew trees. It is used to treat ovarian, advanced non small cell carcinoma, prostate cancer, gastric adenocarninoma, break, head and neck cancer. Paclitaxel 175mg/m over 3 hours once every 3 weeks. Docetaxel 75-100mg/m. the side effects are hair loss, stomach issues, neutropenia is the dose limiting toxicity. Paclitaxel stabilizes microtubules and as a result, interferes with the normal breakdown of the microtubules during cell cycle. Given with docetaxel it forms taxanes. If the chromosomes cant shorted then the chromosomes cant be pulled to dividing cells.

33
Q

How do antimetabolites work?

A
  1. Antimetabolites as competitive substates: the antimetabolite gets incorporated instead of the normal metabolite. They are false substates structurally related to normal cellular components. When they are incorporated into the DNA, they don’t function in the manner they are supposed to, so creates a deficit in the cell which isn’t viable.
  2. Antimetabolites as enzyme Inhibitors: the antimetabolites inhibit the enzymes involved in the synthesis or uptake of a metabolite

Both types of metabolites induce cellular apoptosis and tend to work on the S phase of the cell cycle. Many are nucleic acid base analogues and can get incorporated into the DNA. Eg of drugs are 6-mercaptopurine, 6-thioguanidine

34
Q

What are purines and pyrimadines?

A

Building blocks of DNA

35
Q

How does a cell get its nucleotide?

A
  1. De novo pathway: newly made bases especially to make DNA
  2. Salvage pathway: gets bases from destruction of old DNA and reuse
36
Q

How do purine analogues work?

A

Incorporating these bases, acts as an inhibitor, so the DNA chain cant grow, the cell cant duplicate its chromosomes and the cell cant divide so the cell dies.

37
Q

Give examples of purine analogues and its mechanism of action

A

6-thioguanine: a mimetic of guanine base. Rather that having an oxygen it has a sulhydro group. This base is cytotoxic when it get incorporated into the growing chain. This means we cant continue to make the GMP base.

Mercaptopurine:
Acts in a very similar manner and prevents the synthesis of guanosine monophosphate. The dose is tablet form 50-75mg/m2 per day. Side effects are nephrotoxicity, leucopoenia, vomiting

38
Q

Name pyramidine analogues and its mechanism of action

A

5-Fluorouacil causses inhibition of pyrimidine synthesis. 5-Fluorouacil very closely looks like cytosine, but it has a fluorine group. This is toxic, the cell cant undergo the conversion of DNA to RNA so its toxic. The DNA chain cant grow and the cell dies. 5FU is converted to 5-dUMP which competes with deoxy monophosphate for the enzyme thymidylate synthase. It is commonly used in breast, colorectal, ovarian and skin cancer. It has resistance mechanisms. It increased cellular content of thymidylate synthetase and decrease affinity of thymidylate synthetase.

39
Q

What is methotrexate used for?

A
  • Wide range of solid cancers
  • Gestational choriocarcinoma
  • Acute lymphocytic leukaemia
  • Osteogenic sarcoma
40
Q

What are the resistance mechanisms of methotrexate?

A
  • Cancer cells alter the cellular uptake pathway so that they are wanting to take up folic acid more than methotrexate
  • Increase the expression of the enzyme DHFR that’s inhibited by methotrexate
  • They also create mutations in the enzymes so there’s reduced affinity of DHFR for methotrexate
41
Q

What is the formulation of methotrexate for cancer patients?

A
  • Oral
  • IV; intramuscular or intrathecally
42
Q

What are the side effects of methotrexate? and what are patients given to prevent the side effects

A
  • Myelosuppression, mucositis, rarely pneumonia
  • Contraindicated if renally impaired or severe hepatic impairment
    Patients often given folinic acid, helps prevent side effects

4. 21 (6 decks)

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