Lecture 4: Cancer chemotherapy Flashcards
What are the types of cancer treatment?
- Surgery – non spread tumour
- Radiation – non spread tumour
- Chemotherapy – spread tumour
- Biological therapies (cell therapy, immuno-modulators)
- Targeted therapy
- Gene therapy
- Natural products
How does chemotherapy work?
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)
What are the problems with chemotherapy?
- 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)
What are the 5 major classes of chemotherapy agents?
- 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.
What is the site of action of cytotoxic agents at cellular levels?
- antimetabolites: DNA synthesis
- Alkylating agents: DNA
- Intercalating agents: DNA transcription and DNa duplication
- Spindle poisoms: Mitosis
What is alkylation and how do alkylating agents work?
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.
What are the consequences of alkylating agents?
- 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
What are the groups of alkylating agents?
- Nitrogen mustards
- Ethylenimes
- Alkylsulfonates
- Piperazines
- Nitrosureas
How do mustards work?
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.
Give examples of mustards
- 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)
What are the contraindications and side effects of mustards?
Contraindications are pregnancy and breast feeding. Side effects are nausea/ vomiting, myelosuppression, tissue damage, burning sensation in the injection site
What are the uses for nitrogen mustard?
- Hodgekins disease
- Non hodhekins lymphoma
- Breast
- Ovarian
what causes resistance to alkylating agents?
- 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
What are platinum based drugs most commonly used for?
treatment of ovarian, testicular, lung, bladder, cervical and head and neck cancer.
How do platinum based drugs work?
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
Give names of platinum based drugs and what they are used for
- Cisplatin
- Carboplatin (ovarian and small lung cancer)
- Oxaliplatin (Colon cancer)
- Nedaplatin
- Heptaplatin (gastrin cancer)
- Lobaplatin (Testicular cancer)
- Satraplatin (Prostate cancer)
- Picoplatin (Solid tumours)
What is the effect of cisplatin binding to DNA?
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
What are the mechanism of drug resistance of cisplatin?
- 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
What are the side effects of cisplatin?
- 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
What is the dose limiting factor of cisplatin?
It is nephrotoxic
How does chemotherapy cause nausea and vomiting?
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
What is carboplatin?
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
What are the mechanisms to overcome resistance of platinums?
- 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.
What are anthracycline based drugs - intercalating drugs?
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.
