Therapeutic Classes of Drugs for the Treatment of Cancer; Cytotoxic Therapy Flashcards
What are the different chemotoxic approaches availible for cancer treatment? What stages of the cell cycle do they interfere with?
S-phase; DNA synthesis:
- Alkylating-like Agents
- Antimetabolites
- Topoisomerase Inhibitors
M-phase; mitosis:
- Microtubule Poisons
What are the origins of chemotherapy?
- Soldiers exposed to mustard gas on the German battlefield during WWI
- Compounds caused DNA alkylation; preventing cell division, leading to apoptosis (bone marrow was destroyed)
How does chemotherapy work? What stages do they target?
- Cytotoxic chemotherapy interferes primarily with tumours at the cellular level, by interrupting cell cycle processes
- Drugs interfere w/DNA synthesis and mitotic processes (S and M phases of cell cycle)
What are the disadvantages of chemotherapy?
- Cytotoxic agents do not distinguish between normal and cancer cells
- ADRs to chemotherapy are a consequence of cytotoxicity to normal cells
What are the general adverse effects of chemotherapy (that can be applied to all 4 classes of cytotoxics)?
- Neutropenia, anaemia and thrombocytopenia (platelet deficiency) (collectively = myelosuppression)
- Increased risk of infection
- N&V (GIT cells)
- Diarrhea and mucositis (pain and inflammation of mucus layers that line digestive system) (GIT cells)
- Alopecia (hair)
- Sterility/infertility; potentially infertile, hold sperm/egg in banks instead.
Which ‘normal’ cells are susceptive to chemotherapy drugs given their active multiplication?
Rapidly dividing cells:
- Bone marrow (generates blood cells; immune/Hb)
- GI tract
- Hair follicles
What are some examples of alkylating-like agents?
- Cisplatin
- Carboplatin
- Cyclophosphamide
How do alkylating-like agents work?
- Binds to DNA and cause intra-strand cross linking (causes a conformational change; on same strand of DNA)
> Bind specific sites on purine (A, G) bases of DNA
> Prevents cell division, causes cell death
> Impairs DNA replication and synthesis (S Phase)
> Cytotoxicity targeted to rapidly proliferating cells
How do alkylating-like agents link to DNA?
- Via a platinum atom (not a carbon atom; that’s alkylating agents)
- Not simply an alkyl group consisting of C/H; hence alkylating-LIKE
How do alkylating-like agents cause DNA damage?
- Affect cell cycle in S phase (blocking DNA synthesis)
- Cross-links the 2 strands (of purine bases)
How commonly are alkylating-like agents used? What for?
One of most widely used classes:
- Brain
- Breast
- Bladder
- Cervix
- Endometrium
- Lung
- Testis
- Ovary
- Multiple myeloma
What are the adverse effects associated with alkylating-like agents (on top of the general adverse effects for all cytotoxics), and how do they come about?
Nephrotoxicity
- Result of uptake by PCT cells of nephron
- Controlled by diuretics and pre-hydration (saline, mannitol etc.)
Neurotoxicity
- Dose-limiting side effect
- Acts on the dorsal root ganglion to cause both transient and chronic neuropathies
Peripheral neuropathy e.g. cochlear:
- Damage to outer hair cells of the cochlea (inner ear), resulting in functional deficits due to production of reactive oxygen species
- Can result in loss of hearing
What are some examples of antimetabolites?
- Methotrexate (MTX)
- 5-Fluoruracil (5-FU)
- Gemcitabine
- Mercaptopurine
How do antimetabolites work? What stage of the cell cycle do they effect?
Interference with nucleotide/DNA synthesis:
- MTX is folate antagonist
- Fluoruracil = analogue of uracil, results in generation of a nonsense nucleotide
»> DNA produced is ‘rubbished’
DNA damage:
- Affects cell cycle in S phase; blocks DNA synthesis (S phase for Synthesis)
How does MTX work?
- Folic acid required for normal DNA synthesis and repair
(function to transport carbon for methylation reactions and nucleic acid synthesis) - MTX is structural analogue of folic acid; acts as inhibitor by binding to DHFR (dihydrofolate reductase), preventing production of thymidine (A-T, G-C)
»> Impairs nucleic acid synthesis (T), therefore inhibits DNA, RNA and protein production
What are antimetabolites used to treat? How are they given?
Used to treat:
- Leukaemia, lymphoma (circulating cancer)
- Solid tumours: breast, head and neck, lung, bladder, oesophagus
> > > Given alone or with other chemotherapeutic agents. (e.g. w/alkylating-like agents)
Routes: MTX can be given by PO, IV, SC, IM, intra-arterial, intrathecal (e.g. dysphagia/v. ill)
What are the adverse effects associated with antimetabolites (on top of the general adverse effects for all cytotoxics), and how do they come about?
Nephrotoxicity:
- Cytotoxic to cells in kidney nephrons
Hepatotoxicity:
- Causes fibrosis and increases risk of cirrhosis
Pulmonary toxicity:
- Less common (can be fatal)
- Fever, dry cough, dyspnea (difficult/laboured breathing), chest pain; pulmonary failure
Neurotoxicity:
- Chronic demyelinating encephalopathy w/dementia
- Motor paralysis, seizures, aphasia (loss of ability to understand/express speech), stroke-like symptoms
»> Symptoms NOT mild
Topoisomerase I; what are they?
- Topoisomerase I are enzymes that regulate DNA supercoiling, causing single strand breaks; cutting one strand, passing the other through, then re-ligating; releasing tension from the double helix (now has one fewer twist)
- DNA is supercoiled double helix in cells; must unwind during transcription and replication
How do Topoisomerase I Inhibitors work? Example?
E.g. Topotecan
- Direct anti-cancer effect on DNA
- Topotecan intercalates between DNA bases; blocks unwinding process
- Interferes w/DNA structure
- Impairs DNA replication and synthesis (S phase), leading to cell death
- Cytotoxicity targeted to all rapidly proliferating cells (as with other classes)
What is Topoisomerase II?
- Enzymes that regulate DNA supercoiling, causing simultaneous cleavage of BOTH strands of DNA helix, allowing another double strand to pass through, before re-ligation; managing DNA tangles/supercoils ‘overwinding’ etc
- Can remove supercoiling two twists at a time to yield a ‘relaxed circle’
- Process involving hydrolysis of ATO
How do Topoisomerase II Inhibitors work? Example?
E.g. Doxorubicin
- Anthracycline antibiotic
> Inhibits Topoisomerase II activity (inhibits re-ligation; thus producing just ds-breaks in DNA - cytotoxic effect)
> Binds strongly to dsDNA by intercalation selectively at C-G sequences, blocking synthesis of RNA and thus DNA
(planar anthracycline rings insert between successive base pairs; intercalation)
> Generates free radicals
> Binds to cellular membranes to alter fluidity and ion transport = cell death (of normal AND cancer cells)
What are the adverse effects associated with topoisomerase II inhibitors (Doxorubicin)? How do these occur?
Doxorubicin:
Main S/E is cardiotoxicity (dose-limiting):
- Dilative cardiomyopathy and CHF are cumulative adverse effects that generally appear after 1 year
- Caused by disruption of sarcomere structure; resulting myofilament disorganisation within cardiomyocyte
- Genotoxic stress, mitochondrial dysfunction and oxidation of cellular components lead to activation of protein degradation and suppression of sarcomeric synthesis.
How do Topoisomerase Inhibitors/Cytotoxic Antibiotics (anthracyclines etc.) exert their anti-cancer effect in general? Which stage do they target?
Interference with DNA and RNA synthesis:
- Inhibition of Topoisomerase I or II activity
DNA damage:
- Affect cell cycle in S phase (blocks DNA Synthesis)
When are Topoisomerase Inhibitors/Cytotoxic antibiotics used?
Indications:
- Leukaemia, lymphoma (bloodborne)
- Solid tumours: breast, head and neck, lung, bladder, oesophagus, gastric and ovarian cancer
What are some examples of Microtubule Poisons? What are they? Which stage do they target?
- Antineoplastics (acting to prevent, inhibit or halt the development of a neoplasm (a tumor))
- Vincristine, Vinblastine
- Blocks cell cycle during M Phase (Mitosis)
What is Vincristine, and how does it work?
- Microtubule Poison (Vinka Alkaloid)
- Derivative of periwinkle plant
Mechanism:
- Binds to tubulin structures and prevents polymerisation into microtubules (chromosomes aren’t lined up on mitotic spindle, don’t pull apart properly)
- Inhibits crucial step in cell division process
What has Vincristine (Microtubule Poison) been combined with to treat ALL (Acute Lymphoblastic Leukaemia) in children? What other indications?
- Combined with prednisone
- Treatment of acute lymphoblastic leukaemia in children
- Also active in haematologic malignancies:
> Hodgkin’s lymphomas
> Multiple myeloma
What are the adverse effects associated with the Microtubule Poison, Vincristine?
Cardiovascular:
- Orthostatic hypotension (due to neurotoxicity; autonomic dysfunction, baroreceptors don’t function as well)
Peripheral neuropathy (CNS):
- Paresthesias (tingling in hands/constant pins and needles, potentially painful)
- Neuropathic pain (motor nerve damage w/long-term use)
Gastrointestinal:
- Constipation (as well as N&V of the general S/Es)
