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B33CAN - Pharmacology & Therapeutics > Therapeutic Classes of Drugs for the Treatment of Cancer; Cytotoxic Therapy > Flashcards

Therapeutic Classes of Drugs for the Treatment of Cancer; Cytotoxic Therapy Flashcards

1
Q

What are the different chemotoxic approaches availible for cancer treatment? What stages of the cell cycle do they interfere with?

A

S-phase; DNA synthesis:

  • Alkylating-like Agents
  • Antimetabolites
  • Topoisomerase Inhibitors

M-phase; mitosis:
- Microtubule Poisons

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2
Q

What are the origins of chemotherapy?

A
  • 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)
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3
Q

How does chemotherapy work? What stages do they target?

A
  • 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)
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4
Q

What are the disadvantages of chemotherapy?

A
  • Cytotoxic agents do not distinguish between normal and cancer cells
  • ADRs to chemotherapy are a consequence of cytotoxicity to normal cells
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5
Q

What are the general adverse effects of chemotherapy (that can be applied to all 4 classes of cytotoxics)?

A
  • 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.
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6
Q

Which ‘normal’ cells are susceptive to chemotherapy drugs given their active multiplication?

A

Rapidly dividing cells:

  • Bone marrow (generates blood cells; immune/Hb)
  • GI tract
  • Hair follicles
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7
Q

What are some examples of alkylating-like agents?

A
  • Cisplatin
  • Carboplatin
  • Cyclophosphamide
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8
Q

How do alkylating-like agents work?

A
  • 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
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9
Q

How do alkylating-like agents link to DNA?

A
  • Via a platinum atom (not a carbon atom; that’s alkylating agents)
  • Not simply an alkyl group consisting of C/H; hence alkylating-LIKE
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10
Q

How do alkylating-like agents cause DNA damage?

A
  • Affect cell cycle in S phase (blocking DNA synthesis)

- Cross-links the 2 strands (of purine bases)

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11
Q

How commonly are alkylating-like agents used? What for?

A

One of most widely used classes:

  • Brain
  • Breast
  • Bladder
  • Cervix
  • Endometrium
  • Lung
  • Testis
  • Ovary
  • Multiple myeloma
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12
Q

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?

A

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
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13
Q

What are some examples of antimetabolites?

A
  • Methotrexate (MTX)
  • 5-Fluoruracil (5-FU)
  • Gemcitabine
  • Mercaptopurine
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14
Q

How do antimetabolites work? What stage of the cell cycle do they effect?

A

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)

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15
Q

How does MTX work?

A
  • 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
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16
Q

What are antimetabolites used to treat? How are they given?

A

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)

17
Q

What are the adverse effects associated with antimetabolites (on top of the general adverse effects for all cytotoxics), and how do they come about?

A

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

18
Q

Topoisomerase I; what are they?

A
  • 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
19
Q

How do Topoisomerase I Inhibitors work? Example?

A

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)
20
Q

What is Topoisomerase II?

A
  • 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
21
Q

How do Topoisomerase II Inhibitors work? Example?

A

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)

22
Q

What are the adverse effects associated with topoisomerase II inhibitors (Doxorubicin)? How do these occur?

A

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.

23
Q

How do Topoisomerase Inhibitors/Cytotoxic Antibiotics (anthracyclines etc.) exert their anti-cancer effect in general? Which stage do they target?

A

Interference with DNA and RNA synthesis:
- Inhibition of Topoisomerase I or II activity

DNA damage:
- Affect cell cycle in S phase (blocks DNA Synthesis)

24
Q

When are Topoisomerase Inhibitors/Cytotoxic antibiotics used?

A

Indications:

  • Leukaemia, lymphoma (bloodborne)
  • Solid tumours: breast, head and neck, lung, bladder, oesophagus, gastric and ovarian cancer
25
Q

What are some examples of Microtubule Poisons? What are they? Which stage do they target?

A
  • Antineoplastics (acting to prevent, inhibit or halt the development of a neoplasm (a tumor))
  • Vincristine, Vinblastine
  • Blocks cell cycle during M Phase (Mitosis)
26
Q

What is Vincristine, and how does it work?

A
  • 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
27
Q

What has Vincristine (Microtubule Poison) been combined with to treat ALL (Acute Lymphoblastic Leukaemia) in children? What other indications?

A
  • Combined with prednisone
  • Treatment of acute lymphoblastic leukaemia in children
  • Also active in haematologic malignancies:
    > Hodgkin’s lymphomas
    > Multiple myeloma
28
Q

What are the adverse effects associated with the Microtubule Poison, Vincristine?

A

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)

B33CAN - Pharmacology & Therapeutics (4 decks)

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