Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

LSM4214 Cancer Pharmacology > L2 Chemotherapy > Flashcards

L2 Chemotherapy Flashcards

1
Q

History of chemotherapy

A

1940 - 1950:
- Goodman and Gilman reasoned that this agent could be used to treat lymphoma, since lymphoma is a tumour of lymphoid cells
- Set up animal model, establish lymphoma in mice and treat with mustard gas
- Collab with thoracic surgeon, injected a related agent (mustine) into a patient with Non-Hodgkins lymphoma. Observed dramatic reduction in patient’s tumour mass
- Even though effect only lasted a few weeks (transient), first step to realising that cancer can be treated with pharmacological agents.
- Before chemotherapy, they only had surgery/radiotherapy

1965: Combination therapy
- Cancer cells could conceivably mutate to become resistant to a single agent.
- But using different drugs concurrently would make it extremely difficult for the tumour to develop resistance to the combination.
- Can use combination therapy with non-overlapping therapeutic action
- Induced long term remission in children with acute lymphoblastic leukemia (ALL).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Characteristics of chemotherapy

A
  • Prevent cancer cells from multiplying, invading, metastasize [Targeting tissue invasion/metastasis + enhanced GF hallmarks]
  • Effectiveness mainly on cell multiplication and tumour growth
  • Esp affects cells with rapid rate of turnover
  • Most agents affect synthesis and function (DNA rep, RNA transcription, protein synthesis) → target main macromolecules
  • Agents classified roughly on their activities related to cell cycle
  • **Effectively given: Marked effect with minimal toxicity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Basic concepts in designing therapy drugs - Knowing the target (enemy); Tumour cells

A

Consist of subpopulation:
- Non-dividing terminally differentiated cells (Can divide but not at the moment, 5-10%)
- Continually proliferating cells (access to nutrients, 85-90%)
- Resting cells (low %)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Basic concepts in designing therapy drugs - Knowing the target (enemy); Factors for tumour growth

A
  • Growth fraction: Depends on actively growing fraction of tumour
  • Tumour doubling time: Shorter double time, more aggressive
  • Rate of cell loss due to immune system’s activity, tumour shedding, apoptosis and necrosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Basic concepts in designing therapy drugs - Knowing the target (enemy); Size of detectable tumour

A
  • Most cases: Tumour becomes detectable when there is at least 10^9 cells (1gm)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Basic concepts in designing therapy drugs - Proposed solution; History

A
  • In the mid-1960s, group headed by Howard Skipper at the Kettering-Meyer Lab affiliated with Sloan-Kettering Institute, Southern Research Institute in Birmingham, Alabama, published a series of reports on the criteria of ‘curability’ and on the kinetic behaviour of leukemia cells in mice and the effects of anticancer chemotherapy
  • Principles put forward were derived from behaviour of bacterial cell populations exposed to anticancer agents and based on expt findings in mice bearing; implanted L1210/P388 leukemia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Basic concepts in designing therapy drugs - ___ Model

A
  • Skipper-Schabel model of tumour growth
  • One living leukemia cell can be lethal to the host; hence to cure experimental leukemia, it is necessary to kill every leukemia cell in the mouse, regardless of the number, anatomic distribution, or metabolic heterogeneity (Warburg effect), with treatment that spares the host (minimal toxicity)
  • Percentage, not absolute no., of in vivo leukemia cell populations of various sizes killed by a given dose of a given drug is reasonably constant. The phenomenon of a constant fractional (or %) drug kill of a cell population, regardless of the population size, has been observed repeatedly. Eg. 5mg - 20% killed, 10mg - 40% killed
  • Percentage of experimental leukemic cell populations of any size killed by single-dose treatment of drug to the host is directly proportional to the dose level of the drug (ie. the higher the dose, the higher the percentage cell kill).
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Chemotherapy - based on Gompertzian model

A

Chemotherapy works best in low disease burden as in early stages of cancer (rapid growth stage) vs late stage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

___ Model of tumour growth

A
  • Gompertzian model
  • Growth-growth rate of tumour cells decreases with time
  • Maximum response to chemotherapy is during rapid growth phase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

___ Hypothesis

A
  • Goldie-Coldman
  • Fraction of tumour cells will develop resistance after treatment
  • This clone will continue to grow even though the patient appears to respond
  • Alternating combinations of chemotherapy agents early in the treatment is necessary to prevent development of resistant clones
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is conventional chemotherapy used for?

A
  • Cure patients (early stage)
  • Prolong survival (by 5-10 years)
  • Palliative care (late stage; reduce symptoms eg. pain/inflammation)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Types of chemotherapy

A

1) Adjuvant chemotherapy
- May be given after potentially curative treatment
- Surgery for breast cancer (to remove tumour) + chemo to kill off remaining CC
- Radiotherapy for lymphomas/leukemias + chemo

2) Neoadjuvant therapy
- Administration of chemotherapy to shrink tumour before it is removed surgically
- eg. colorectal and gynaecological cancers

3) Induction therapy
- Therapy given as primary treatment for disease (first treatment given for a disease before eg. other treatments; surgery/chemo/radiotherapy)
- eg. leukemias/lymphomas

4) Palliative
- Symptom control; pain control when previous therapy has failed or disease relapsed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Goals for combination therapy

A
  • Maximum cell kill with tolerable toxicity
  • Broad coverage of resistant cell lines
  • Prevent development of resistance
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Method for combination therapy

A
  • Use only effective drugs (not overlapping MOA)
  • Use optimal scheduling and dose
  • Limit overlapping toxicities (can decrease toxicity by taking another drug)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Disadvantages of chemotherapy

A
  • Multiple toxicities
  • Reduction or holding of doses due to toxicity, limiting effectiveness
  • Complicated to administer (iv + oral etc)
  • Expensive
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Side effects of chemotherapy

A
  • Both normal and cancer cells multiply (not targeted)
  • Chemotherapy affects cells with high growth fraction; hence would affect normal tissues with high growth fraction eg. bone marrow, hair follicles, GI mucosa, skin
  • Myelosupression: Decreased WBC, RBC, platelets
  • Alopecia (hair loss)
  • Mucositis (inflammation and ulceration of mucous membranes lining digestive tract)
  • Nausea and vomiting (enemis) due to stimulation of vomiting centre in CNS and stimulation of nerves in GI tract
  • Onset and duration of emesis vary with drug; low dose, slower onset
  • Other SE: Diarrhoea, Cystitis (UTI), Sterility, Myalgia (muscle aches/pain), neuropathy, local reaction, phlebitis (inflamed vein near skin)
  • More severe SE: Pulmonary fibrosis, cardiotoxicity, renal failure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Classification of chemo drugs

A

1) Cell cycle specific
- Antimetabolites
- Bleomycin (Special class of cytotoxic Ab under CCS)
- Plant alkaloids
- Podophyllin alkaloids

2) Cell cycle non specific
- Alkylating agents
- Cytotoxic antibodies
- Cisplatin
- Nitrosoureas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Drug prototypes of purine antagonists

A
  • Mercaptopurine
  • Thioguanine
  • Fludarabine phosphate
  • Cladribine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

MOA of purine antagonists/mercaptopurine

A
  • 6-mercaptopurine metabolized by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to nucleotide 6-mercaptopurine ribose phosphate/6-mercaptopurine ribonucleotide
  • 6-mercaptopurine ribose phosphate/6-mercaptopurine ribonucleotide are cytotoxic as they inhibit de novo purine biosynthesis
  • Block the amidotransferase in the first step of purine biosynthesis, namely the formation of 5-phosphoribosylamine by feedback mechanism
  • Tldr; inhibits numerous enzymes of purine nucleotide interconversion -> stops DNA synthesis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

MOA of anthracycline antibiotics

A
  • Cell cycle non specific
  • Apply to doxorubicin and daunorubicin
  • Mechanism 1: Inhibits DNA and RNA synthesis by intercalating (planar aromatic moiety of a small molecule is inserted between a pair of base pairs) between bp of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells
  • Inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA, thus blocking DNA transcription and replication
  • Mechanism 2: Creates free oxygen radicals that damage the DNA and cell membranes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

SE of anthracycline antibiotics

A
  • Cardiotoxicity due to free radical production
  • Alopecia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

MOA of dactinomycin/actinomycin D

A
  • First Ab isolated by Selman Waksman in 1940
  • Intercalates in DNA minor grooves between adjacent GC path
  • Prevent elongation by RNA pol and inhibits transcription
  • Inhibits topoisomerase II
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Which cancers for cytotoxic antibodies

A
  • Doxorubicin - **breast, **ovarian, **liver, genitourinary, gastrointestinal, lymphomas and soft tissue sarcoma, and hematologic cancers
  • Daunorubicin - Leukemias, lymphomas, lymphoproliferative disorders
  • Dactinomycin - certain types of testicular cancer, a type of ovarian cancer
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Drug prototypes under alkylating-like agents

A
  • Similar MOA to alkylating agents but missing alkyl groups
  • Procarbazine
  • Dacarbazine
  • Altretamine
  • **Cisplatin
  • **Carboplatin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Side effects of platinum analogues

A

Renal, N/V (emesis)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

(CCS) Subclass of plant alkaloids + drug prototype

A
  • Vinca alkaloids; Vinblastine
  • Taxanes; Paclitaxel (slightly different MOA from vinca alkaloids)
  • Podophyllotoxins; Epotoside
  • Camptothecins; Topotecan
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

MOA of Vinca alkaloids (known as spindle poison)

A
  • Binds to microtubule protein tubulin in a dimeric form
  • Drug-tubulin complex adds to the forming end of the microtubules to terminate assembly (bind to tubulin)
  • Microtubules depolymerise
  • (3) Resulting in mitotic arrest in metaphase (M phase), dissolution of mitotic spindle, interference with chromosome segregation
28
Q

Which cancers uses vinca alkaloids?

A

Lymphomas and leukemias

29
Q

Side effects of vinca alkaloids

A
  • Neuropathy (damage to the peripheral nervous system)
  • Alopecia
  • Myelosuppression
  • GI tract
  • Hyponatremia (low Na)
30
Q

MOA of podophyllotoxins

A
  • Blocks cells at the late S-G2 phase by inhibiting topoisomerase II
  • Results in DNA damage through strand breakage by forming ternary complex of drug, DNA and enzymes
31
Q

Which cancers uses podophyllotoxins

A
  • Epotoside: **Lung cancer, testicular cancer, **lymphomas
  • Teniposide: Childhood acute lymphoblastic leukemia (ALL)
32
Q

SE of podophyllotoxins

A
  • Myelosuppression
  • Mucositis
  • GI tract toxicities
33
Q

Drug prototype of taxanes + origin

A
  • Paclitaxel (taxol)
  • Docetaxel
  • Alkaloid esters derived from Yew plant
34
Q

MOA of taxane (known as spindle poisons)

A
  • Binds to ß subunit of tubulin
  • Interferes with normal function of microtubule breakdown and as a result, hyperstabilising microtubule structure
  • Resulting in drug-microtubule complex (paclitaxel-microtubule) not disassembling
  • Affects cell function because the shortening and lengthening of microtubules (aka dynamic stability) is necessary for their functions as a mechanism to transport other cellular components
  • Hence, exposed cells are arrested at the G2-M phase and undergo apoptosis, inhibiting cell division

Paclitaxel is an anticancer drug that targets microtubules. Microtubules consist of cylindrical hollow bodies of about 25–30 nm in diameter, composed of polymers of tubulin in dynamic equilibrium with tubulin heterodimers (consisting of alpha and beta protein subunits) [40,41]. The principal function of microtubules is the formation of the mitotic spindle during cell division. In addition, they are required for the maintenance of cell structure, motility, and cytoplasmic movement within the cell. The synthesis of tubulin and the assembly of microtubules occur during the G2 phase and the prophase of mitosis. Microtubules are in a state of dynamic equilibrium with their subunit tubulinsαandβ, arranged in a head to tail fashion, with preferential faster growth (plus ends) at one end, and slower growth (minus ends) at the other end. Under steady-state conditions, the length of the microtubule is unchanged, as the net tubulin assembly rate equals the net disassembly rate. The minus ends part of microtubule are usually anchored mainly at the centrosome [42], while the plus ends explore the cytoplasm and interact with cellular structures [43,44].
Dr. Horwitz discovered that paclitaxel, unlike vinca alkaloids which prevent microtubule assembly, prevents cell division by promoting the assembly of stable microtubules especially fromβ-tubulin heterodimers and inhibits their depolymerisation; hence, exposed cells are arrested in the G2/M-phase of the cell cycle [45] and eventually undergo apoptosis [46], thereby inhibiting cell replication [40,47].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475536/#:~:text=Mechanism of action of paclitaxel,depending on the dose concentration.

35
Q

Which cancer uses taxanes

A
  • **Lung cancer
  • **Ovarian cancer
  • **Triple -ve breast cancer
  • Head and neck cancer
36
Q

SE of taxanes

A
  • Myelosuppression
  • Alopecia
  • Neuropathy
  • Allergies
37
Q

Taxanes and vinca alkaloids

A
  • Taxanes: prevents cell division by promoting the assembly of stable microtubules especially fromβ-tubulin heterodimers and inhibits their depolymerisation [Cannot depolymerise]
  • Vinca alkaloids: Interfere with assembly of spindle proteins during mitosis [Cannot assemble]
  • Both are named spindle poisons/mitosis poisons, but act in different ways
  • Have to state both MOA when asked about spindle poisons
38
Q

Subclass of antimetabolites + drug prototype

A
  • Folic acid analogs: Methotrexate
  • Purine analogs: Mercaptoguanine
  • Pyrimidine analogs: Fluorouracil
39
Q

Normal functioning of folate + MOA of methotrexate

A
  • Folate: essential dietary factor to form tetrahydrofolate (THF) cofactors to provide single carbon groups for synthesis of precursors of DNA and RNA
  • Folate is reduced by dihydrofolate reductase (DHFR) to tetrahydrofolate (THF) to form cofactor
  • MTX: competitive inhibitor; folic acid analogue that competitively inhibits DHFR by binding to it (catalyse formation of THF from DHF)
  • Prevents formation of THF, causing intracellular deficiency of folate coenzymes and accumulation of toxic inhibitory substrate, DHF polyglutamate (toxic to cell cycle)
  • Ceasing the one carbon transfer reaction for purine and thymidylate synthase (Methotrexate-polyglutamate further inhibits the de novo purine synthesis of both purine and thymidylate synthase), interrupting DNA and RNA synthesis
40
Q

Therapeutic/Cancer use for MTX

A
  • **Breast cancer (Triple -ve)
  • **Burkitt’s and non-Hodgkin’s lymphomas
  • **Ovarian cancer
  • Head and neck cancer
  • Bladder cancer
  • Psoriasis
  • Rheumatoid arthritis
  • Acute lymphoblastic leukemia
  • Meningeal leukemia
  • Choriocarcinoma
  • Osteosarcoma
  • Mycosis fungoides
41
Q

SE of MTX

A
  • Bone marrow suppression (Myelosuppression): Rescue with leucovorin (folinic acid); convert to THF without need of DHFR since it is inhibited
  • Nephrotoxic: Give sodium bicarbonate to alkalinize the urine
42
Q

Cancer use of purine antagonists

A
  • Leukemia (AML/CML)
43
Q

SE of purine antagonists

A
  • Myelosuppression
  • Emesis (N/V)
  • Diarrhoea
44
Q

Drug prototypes of pyrimidine antagonists

A
  • Fluorouracil
  • Gemcitabine
  • Cytarabine
  • Capecitabine
45
Q

MOA of gemcitabine

A
  • MOA 1 [triphosphate form];
  • Deoxycytidine antimetabolite
  • Undergoes intracellular conversion to gemcitabine monophosphate via deoxycytidine kinase (enzyme)
  • Subsequently P to gemcitabine diphosphate and gemcitabine triphosphate
  • Gemcitabine triphosphate competes with deoxycytidine triphosphate (dCTP; building block of DNA), to be incorporated into DNA strands
  • After adding gemcitabine triphosphate into DNA, an additional base pair (add some dCTP) is added before DNA pol is inhibited.
  • Masked termination makes gemcitabine more difficult to remove from DNA strands
  • Gemcitabine inhibits both DNA replication and repair, inducing cell death via apoptosis
  • MOA 2 [diphosphate form];
  • Gemcitabine diphosphate analogue binds to ribonucleotide reductase (RNR) active site and inactivates the enzyme reversibly
  • When RNR is inhibited, cell cannot produce deoxyribonucleotides required for DNA replication and repair, inducing cell apoptosis.
46
Q

Cancer use for gemcitabine

A
  • **Pancreatic cancer (v effective)
  • **small cell lung cancer
  • **Breast cancer
  • **Ovary cancer
  • Bladder cancer
  • Head and neck
  • Kidney cancer
47
Q

SE of gemcitabine

A
  • Neutropenia (decrease neutrophils production)
  • Emesis (N/V)
  • Fever
48
Q

Toxicity of alkylating agent (2)

A

Myelosuppression, alopecia

49
Q

Drug prototypes under cytotoxic antibodies

A
  • **Anthracyclines: Doxorubicin, Daunorubicin
  • *Bleomycin (Cell cycle specific)
  • *Dactinomycin
  • Plicamycin
  • Mitomycin
50
Q

Which cancers use platinum analogues?

A
  • Sarcomas
  • Ovarian cancer
  • Lung cancer
  • Lymphomas
51
Q

Examples of drug under nitrosoureas

A
  • **Carmustine
  • **Streptozocin
  • Lomustine
  • Semustine
52
Q

Cancers using nitrosoureas

A
  • Brain cancer
  • Hodgkin and non hodgkin lymphomas
53
Q

Drug prototypes of vinca alkaloids

A
  • Vinblastine
  • Vincristine
54
Q

MOA of nitrosoureas

A
  • Similar to alkylating agents but slightly different
  • Alkylation of DNA → cross linking/ring cleavage → inhibit DNA synthesis, RNA production and translation → apoptosis
  • carbamylation of lysine residues on glutathione reductase → cell death
  • Can cross blood brain barrier due to high lipid solubility
  • Suitable for brain cancer
55
Q

Drug prototypes (under alkylating agents) for cancer

A
  • Used to treat wide variety of hematologic and solid tumours
  • Ovarian cancer - thiotepa
  • Chronic myeloid leukemia - Busulfan
  • Brain cancer - Nitrosoureas
  • Insulin-secreting islet cell carcinoma of pancreas - Streptozocin
56
Q

What are the platinum analogues? What is their MOA?

A
  • Cisplatin, carboplatin
  • Coordinate to DNA to interfere with DNA repair, by forming interstrand and intrastrand crosslinks in DNA, RNA.
57
Q

Sub class of alkylating agents + drug prototype

A
  • Nitrogen mustards; Cyclophosphamide
  • Ethylenimines; Thiotepa
  • Alkyl sulfonates; Busulfan
  • Nitrosoureas; Carmustine [Similar MOA to alkylating agent, differ slightly]
58
Q

MOA of alkylating agents

A
  • Alkylate within DNA at N7 position of guanine
  • Resulting in miscoding through abnormal base-pairing with thymine (instead of cytosine) to form defective protein OR in depurination by excising guanine residues → strand breakage
  • Could result in cross-linking with DNA OR ring cleavage too
59
Q

Drug prototype of camptothecins

A
  • Topotecan
  • Irinotecan
60
Q

What is the MOA of camptothecins?

A
  • Inhibit in S phase
  • Interfere with topoisomerase I
  • Results in DNA damage
  • Irinotecan: prodrug, metabolized to SN-38, an active topoisomerase I inhibitor
61
Q

Which cancers uses camptothecins

A

Topotecan: **Ovarian and cervical cancers
Irinotecan: **Colorectal cancer in combination with 5-FU (antimetabolite)

62
Q

SE of camptothecins

A
  • Diarrhoea
  • Myelosuppression
63
Q

Drug prototype of podophyllotoxins + origin

A
  • Epotoside
  • Teniposide
  • Semi-synthetic derivatives of podophyllotoxins extracted from the root of the mayapple
64
Q

MOA of 5-FU

A
  • 5-FU metabolically activated to a nucleotide, 5-fluoro-2’-deoxyuridine-5’-monophosphate (FdUMP)
  • Normal function of thymidylate synthase: transfers a methylene group from reduced folic acid to deoxyuridylate monophosphate to form thymidylate, essential for DNA synthesis
  • FdUMP Inhibits thymidylate synthase
  • 5-FU is incorporated into DNA instead, inhibiting DNA synthesis, causing cytotoxicity
  • Cytotoxicity may also be due to incorporation of 5’-fluorouridine triphosphate into RNA, leading to fraudulent RNA formation, inhibiting RNA processing
65
Q

Cancer use for 5-FU

A
  • **Metastatic breast cancer
  • **Hepatoma (liver cancer)
  • **Prostate cancer
  • **Ovary cancer
  • **Cervical cancer
  • Metastatic cancer of GI tract (stomach)
  • Urinary bladder cancer
  • Pancreatic cancer
  • Oropharyngeal areas cancer
66
Q

SE of 5-FU

A
  • Myelosuppression
  • Mucositis
  • Dermatitis
  • Diarrhoea
  • Cardiac toxicity
67
Q

Characteristics of cancer cell (that shapes therapy)

A
  • Cancer cells have none of the normal self regulating controls that non-malignant/normal cells have in place (hallmarks).
  • CC have larger proportion of cells in active growing phase (high growth faction)

LSM4214 Cancer Pharmacology (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions