CPT: Cytotoxic chemotherapy Flashcards

1
Q

Fill in the gap:

Treatmen is either or

A

Treatment is either curative** or **palliative.

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2
Q

What are goals of treatment?

A

Goals of therapy

  • Cure or long-term survival
  • Palliative - improved symptoms control; quality of life
  • Side Effects - reduces Side effects to an “acceptable” level
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3
Q

What main treatment options are available?

What additional treatment options are available?

A

Main Forms of therapy

  • Surgery
  • Chemotherapy
  • Radiotherapy

Other forms of therapy

  • HIFU
  • PDT
  • Laser treatment
  • Cryotherapy
  • Sometimes more than one treatment approach is used. Cure is possible – but only in 35-40%
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4
Q

What are factors affecting selection of treatment?

A

Factors affecting selection:

  • Tumour type
  • Metastases
  • Stage and duration
  • Previous treatment
  • severity and incidence of Side effects
  • Age
  • Sex
  • Concurrent disease
  • Motivation
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5
Q

What do cytotoxic drugs do?

What classes of chemotherapy agents is there?

A
  • Cytotoxic drugs mainly act by damaging the cellular DNA through action on the S phase of the cell cycle. They also interfere with other vital cellular functions. Cell death results.
  • They are NOT specific for tumour cells and affect ALL rapidly dividing tissue cells causing damage to “normal” healthy tissue.

Classes of Chemotherapy agents:

  • Alkylating agents
  • Antimetabolites
  • Vinca alkaloids and Etoposide
    • Cytotoxic antibiotics
    • Miscellaneous
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6
Q

What are drug classes in alkalating agents?

How do these generally work?

A
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7
Q

Mechanism of action of alkylating agents

A

Alkylate within DNA at the N7 (form covalent bonds) position of guanine. This results in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage

Cross-linking of DNA and ring cleavage may also occur

In all this prevents DNA separation and mRNA transcription

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8
Q

What are examples of nitrogen mustards - which are we going to be focusing on?

A

•Cyclophosphamide (Cytoxan)

  • Ifosfamide
  • Mechlorethamine
  • Melphalan
  • Chlorambucil
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9
Q

What can Cyclophosphamide (Cytoxan) be used for?

Side effects?

A

Cyclophosphamide used in lymphocytic leukaemia, lymphomas & solid tumours i.e. ovarian cancer

Side Effects

  • Gametogenesis
  • haemorrhagic cystitis (with high dose cyclophosphmide)
  • prolonged use causes acute non-lymphocytic Leukaemia.
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10
Q

Alkylating-Related Agents examples

A
  • Procarbazine
  • Dacarbazine
  • Altretamine

Platinum compounds:

•Cisplatin

•Carboplatin

•Oxaliplatin

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11
Q

What is the mechanism of action of platinum compounds?

A

Cisplatin/carboplatin:

60-65% intra strand GG diadducts

  • 25-30% intra strand AG diadducts
  • 5-10% intra strand GNG diadducts
  • 1-3% intra strand GG

The mechanism of oxaliplatin has not been fully elucidated.

  • These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity.
  • They chemically react with nucleophillic centres in the DNA with which they form platinum cross-links.
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12
Q

What are side effects of platinum compounds?

A

Cisplatin can cause:

  • severe nausea and vomiting
  • nephrotoxicity
  • ototoxicity
  • peripheral neuropathy
  • hypomagnesaemia
  • myelosuppression

For oxaliplatin neurotoxicity is the dose limiting SE Carboplatin is better tolerated than Cisplatin but myelosuppression is more severe

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13
Q

What are drug classes and examples of drugs for antimetabolites.

What characterisitic does their modes of action have?

A
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14
Q

What are examples of folic acid analogs?

Which is most of intrest to us?

A

•Methotrexate

  • Trimetrexate
  • Pemetrexed
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15
Q

What is folic acid and where is it sourced?

Why is it important and what is its normal pathway?

A

Folate

lAn essential dietary factor, from which THF cofactors are formed which provide single carbon groups for the synthesis of precursors of DNA and RNA

lTo function as a cofactor folate must be reduced by DiHydro Folate (DHF) to TetraHydroFolate (THF)

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16
Q

What is the mechanism of action of methotrexate?

A

Methotrexate resembles dihydrofolate with which it competes for the active site of the enzyme dihydrofolate reductase.

By blocking the enzyme it prevents the formation of tetrahydrofolate which is an essential co-factor for purines and pyrimidines and therefore DNA/RNA.

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17
Q

What is often given with metrotrexate and why?

A
  • Folinic acid is sometimes given 24-36 hours after Methotrexate to limit the damage to normal cells.
    • High-dose regimens must be followed by ‘rescue’ with folinic acid (a form of FH4)
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18
Q

What are side effects of methotrexate and how can some be reduced?

A
  • Nephrotoxic (give sodium bicarbonate to alkalinize the urine)
  • Myelosuppression (Rescue with leucovorin folinic acid)
  • Mucositis - damage to oral cavity
  • Pneumonitis
  • hepatic impairment
19
Q

What is an important point to remember about the dosing regime of methotrexate?

A

•NB: MTX is given ONCE A WEEK whether by injection or orally !!!!!!!!!!!

20
Q

Give examples of purine antagonsists and their mechanism

A
  • The main anticancer purine analogues include fludarabine, pentostatin, cladribine, clofarabrine, nelarabrine, mercaptopurine and thioguanine.
  • Mercaptopurine is converted into fraudulent nucleotide.
  • Fludarabine in its trisphosphate form inhibits DNA polymerase and is myelosuppressive.
  • Pentostatin inhibits adenosine deaminase-a critical pathway in purine metabolism.
21
Q

What are examples of pyridime antagonsists

A
  • Fluorouracil
22
Q

How does flurouracil work?

A
  • Fluorouracil, an analogue of uracil, also interferes with DTMP synthesis.
  • It is converted into a ‘fraudulent’ nucleotide, fluorodeoxyuridine monophosphate (FDUMP). This interacts with thymidylate synthetase but cannot be converted into DTMP.
  • Inhibition of thymidylate sythase blocks DNA production and halts cell division. 5-Fluorouracil is also incorporated into RNA obstructing RNA processing and protein synthesis
23
Q

Describe the mechanism of action of cytarabine

Where are most unwanted effects?

A
  • Cytarabine (cytosine arabinoside) is an analogue of the naturally occurring nucleoside 2’-deoxycytidine.
  • The drug enters the target cell and undergoes the same phosphorylation reactions as the endogenous nucleoside to give cytosine arabinoside trisphosphate, which inhibits DNA polymerase.
  • The main unwanted effects are on the bone marrow and the gastrointestinal tract. It also causes nausea and vomiting.
24
Q

What is gemcitabine an analogue of?

What differetn effects does it have from this analogue?

A
  • Gemcitabine, an analogue of cytarabine, has fewer unwanted actions, mainly an influenza-like syndrome and mild myelotoxicity.
  • It is often given in combination with other drugs such as cisplatin.
25
Q

Side effects of 5-FU

A

Side Effects

  • lBone marrow suppression
  • lDiarrhoea,
  • lMucositis,
26
Q

Describe the mechanism of action of Capecitabine

A
  • Capecitabine is an oral prodrug readily absorbed by the GIT.
  • Metabolized in vivo to fluorouracil in the liver by carboxylesterase and cytidine deaminase and then in the peripheral and tumour tissue by thymidine phosphorylase
  • Thymidine phosphorylase is produced at higher levels in tumour tissue – so higher production of fluorouracil in tumour tissue
27
Q

What are side effects of Capecitabine

A

Side Effects

  • lDiarrhoea
  • lnausea and vomiting
  • labdominal pain,
  • lstomatitis
  • lpalmar-plantar erythrodysesthesia syndrome (erythema and desquamation of hands and feet
28
Q

Examples of plank alkaloids

A
29
Q

Describe the mechanism of action of vinca alkaloids

Where are they derived?

Examples

A
  • The vinca alkaloids are derived from the Madagascar periwinkle (Catharanthus roseus).
  • The principal members of the group are vincristine, vinblastine and vindesine.. Vinrelibine is a semisynthetic form
  • The drugs bind to tubulin and inhibit its polymerisation into microtubules, preventing spindle formation in dividing cells and causing arrest at metaphase in M phase.
  • They also inhibit other cellular activities that involve the microtubules, such as leukocyte phagocytosis and chemotaxis, as well as axonal transport in neurons.
30
Q

Side effects of vinca alkaloids

A

Side Effects

  • central and peripheral (including autonomic) neurotoxicity.
  • Neurological toxicity esp. Vincristine (peripheral parasthesia, loss of deep tendon reflexes, abdominal pain and constipation)
  • Myelosuppression - Vinblastine > Vindesine > Vincristine
  • Intrathecal doses of vinca alkaloids, result in ascending paralysis and death
31
Q

Important condieration when administering vinca alkaloids?

A

NB: NEVER to be given INTRATHECALLY !!!!!!!!

Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled “Do not remove covering until moment of injection. Fatal if given intrathecally. For i.v. use only.”

32
Q

What are examples of Camptothecins

How do they work

Where are they dervived?

A
  • The camptothecins: irinotecan and topotecan, isolated from the stem of the tree Camptotheca acuminata, bind to and inhibit topoisomerase I, high levels of which occur throughout the cell cycle.
  • Irinotecan: a prodrug that is metabolized to an active Top I inhibitor, SN-38
  • Topotecan: semisythetic camptothecan
33
Q

Side effects of:

  1. Topotecan:
  2. lrinotecan:
A

Topotecan:

  • Neutropenia (decr neutrophis)
  • Thrombocytopenia (Dcr platlets)
  • anemia

lrinotecan:

  • Severe diarrhea
  • myelosuppression
34
Q

What cancers are topotecan and Irinotecan used for

A
  • Topotecan -second line treatment for ovarian cancer.
  • Irinotecan - used in conjunction with targeted biotherapies for advanced colorectal cancer
35
Q

Podophyllotoxins examples and mechanism

A

Etoposide (VP-16): is derived from mandrake root (Podophyllum peltatum):

  • •Blocks cells in the late S-G2 phase of the cell cycle through inhibition of topoisomerase II
  • •Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme
  • Used in lung cancer

Teniposide (VM-26): also an ihibitor of topoisomerase II and acts in a similar manner to Etoposide.

36
Q

Podophyllotoxins side effects

A
  • Myelosuppression
    • Leucopenia,
    • Thrombocytopenia
    • Anaemia.
  • Nausea and vomiting
  • Anorexia
  • Diarrhoea
  • Mucositis
37
Q

Where are taxenes dervived?

Examples and mechanisms

A
  • The taxanes are derived from a naturally occurring compound found in the bark of the yew tree (Taxus spp).
  • They act on microtubules, stabilising them (in effect ‘freezing’ them) in the polymerised state (known as spindle poisons), achieving a similar effect to that of the vinca alkaloids.

  • Paclitaxel (Taxol)
  • Docetaxel (Taxotere)
38
Q

Side effects of:

  • Paclitaxel
  • Docetaxel
A

Paclitaxel

  • •Neutropenia
  • •thrombocytopenia
  • •Peripheral neuropathy

Docetaxel

  • •Bone marrow suppression
  • •Neurotoxicity
  • •Fluid retention
  • Hypersensitivity reaction (SEE BNF)
39
Q

How do anthracyclic AB bind to DNA?

What are examples of these cytotoxic ABs?

How do they produce their effects - what should they not be given with?

A
  • Athracyclines are anthraquinones originally isolated from Streptomyces peucetius.
  • Known for binding to DNA through intercalation due to planar anthracycline chromophore
  • The main anticancer anthracycline antibiotic is doxorubicin.
  • Other related compounds include idarubicin, daunorubicin, epirubicin and mitoxantrone (mitozantrone).

Cytotoxic antibiotics mainly produce their effects through direct action on DNA. As a rule, they should not be given together with radiotherapy, as the cumulative burden of toxicity is very high

40
Q

Describe the MOA of Doxorubicin:

A

Doxorubicin: inhibits DNA and RNA synthesis; the DNA effect is mainly through interference with topoisomerase II action.

Mechanism of Action

  • High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis
  • DNA strand scission via effects on Top II
  • Binding to membranes altering fluidity
  • Generation of the semiquinone free radical and oxygen radicals
41
Q

Side effects of Doxorubicin

A

Side Effects

  • Bone marrow depression
  • Total alopecia
  • Cardiac toxicity*

* due to lGeneration of the semiquinone free radical and oxygen radicals

42
Q

Mechanism of action of Bleomycin and Mitomycin C

Side effects of both

A
  • Mitomycin C - Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA
  • Side effect: delayed cumulative bone-marrow suppression
  • Bleomycin generates free radicals which will cause fragmentation of the DNA chain. It is most effective in the G2 phase but is also active against non-dividing cells i.e. cells in the G0 phase.
  • The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations.
  • Side effect mainly involve skin and mucous membranes:
43
Q

When is chemotherapy given?

A

•Normally chemotherapy is given every 3-4 weeks (21-28days). This intermittent delivery allows the proliferating body tissue (e.g. bone marrow) to recover while still inflicting damage to the tumour.

•Treatment may be delayed by a week if the patients blood counts have not yet recovered. This short delay is not deleterious but care must be taken not to allow the interval to become too long.

•Most regimens use 3-6 treatment cycles (depending on the tumour type).

44
Q

Response to chemotherapy

A
  • Good response (potentially curable) - Hodgkin’s disease, acute leukaemia’s, childhood cancer, testicular cancer
  • Good response but may relapse - Breast cancer, Bladder cancer, chronic leukaemia’s.
  • Poor response - GI cancer, Renal cancer, Pancreatic cancer, Gliomas