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233 FINAL > Chemotherapy Drugs: Monoclonal Antibodies & Kinase Inhibitors > Flashcards

Chemotherapy Drugs: Monoclonal Antibodies & Kinase Inhibitors Flashcards

1
Q

Cancer Chemo Part 2

Please refer to M phase Specific & S Phase Specific diagram

M phase specific :
S phase specific:
Agents Affecting Multiple Phases of Cell Cycle
Cell Cycle Independent

A

M phase specific :

  • Antimicrotubule agents: inhibit fxn of microtubules
  • Topoisomerase II inhibitors (also S phase), block topoisomerase fxn (unwinding DNA)

S phase specific:

  • Antimetabolites: inhibit DNA synthesis
  • Topoisomerase II inhibitors

Agents Affecting Multiple Phases of Cell Cycle
- antitumor antibiotics: induce DNA lesions, inhibit topo

Cell Cycle Independent
- alkylating agents: crosslink guanine nucleobases in DNA

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2
Q

What are the 2 types of plant based compounds?

Familiar with how they work

A
  1. Paclitaxel
    – Are naturally occurring compounds found in the
    bark of the pacific yew tree. These agents act on
    microtubules, stabilizing and “freezing” them in a
    polymerized state. This results in cell cycle arrest
    and apoptosis.
    – Adverse effects include bone marrow suppression
    and neurotoxicity (independently, off target fx)
  2. Etoposide
    – Derived from the mandrake root and similar to
    doxorubicin (previous lecture) this compound
    interacts with DNA and inhibits Topoisomerase II .
    – Adverse effects include nausea and vomiting, hair
    loss, bone marrow suppression and cardiotoxicity
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3
Q

Name the 4 types of hormones

A
  • Glucocorticoids - Lymphomas specifically
  • Tamoxifen - Inhibit transc factors, certain breast cancers

• Antiandrogens: Prostate cancer
Once diagnosed, just want to stabilize
These drugs decrease testosterone to prevent tumors from growing

• Aromatase Inhibitors: more specific, breast cancer in post menopause

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4
Q

Matching the 4 types of hormones for their treatment usage:
1. Glucocorticoids __, 2. Tamoxifen __. 3. Antiandrogens __, 4. Aromatase Inhibitors __

A. Is an antioestrogen and effective in the treatment of hormone-dependent breast cancer. Mechanistically inhibits the transcription of oestrogen-responsive genes, by blocking the oestrogen receptors.

B. Anastrozole, letrozole and exemestane suppress the synthesis of oestrogen from androgens in the adrenal cortex. Effective in the treatment of breast cancer in postmenopausal women.

C. Prednisolone can inhibit lymphocyte proliferation and are used in the treatment of leukaemias & lymphomas.

D. Flutamide, cyproterone and bicalutamide are used for treatment of prostate tumours.

A
  1. Glucocorticoids - C
  2. Tamoxifen - A
  3. Antiandrogens - D
  4. Aromatase Inhibitors - B
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5
Q

What are the 2 types of Antimicrotubules?

Don’t need to know these drugs
Inhibit microtubules

A

• Vinca Alkloids
– Vincristine (Lymphoma, Breast)
– Vinblastine (Lymphoma)
– Vinorelbine (Breast, Lung)

• Taxanes
– **Paclitaxel (Breast, Lung)
– Docetaxel (Breast, Prostate)
– Nab-Paclitaxel (Breast)

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6
Q

Why is monoclonal antibodies better than most cytotoxic drugs and what is one of the challenges?

A
  • Monoclonal antibodies offer better selectivity towards the tumours without many of the side effects of conventional chemotherapy.
  • One of the challenges is the high cost associated with this drug class.
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7
Q

List the 4 types of monoclonal antibodies:

A
  • Rituximab
  • Trastuzumab
  • Bevacizumab
  • Catumaxomab
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8
Q

Which types of monoclonal antibodies does the following:
1. Attaches the EpCAM which is overexpressed in some malignant cells. Activates immune cells to clear cancer cells.

  1. Binds to CD20 (calcium-channel forming protein), which is preferentially expressed on B-cells and kills them. Used for treatmentof lymphoma, including Hodgkins lymphoma.
  2. Used for the treatment of colorectal cancer. It neutralizes VEGF thereby preventing angiogenesis (blood vessel formation).
  3. (Herceptin) is a humanized murine monoclonal antibody that inhibits an oncogenic receptor HER2 (human epidermal growth factor receptor 2). It gives a 79% 1-year survival rate in treatment of patients with
    aggressive form of breast cancer.
A
  1. Catumaxomab
  2. Rituximab (Unable to pass thorugh cell membrane
    Nno longer get oxygen or nutrients)
  3. Bevacizumab
  4. Trastuzumab
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9
Q

What are the side effects when using the monoclonal antibodies?

A

• Hypotension
• Chills and Fever during the initial fusions and
subsequent hypersensitivity reactions. (IV)
• Cardiotoxicity (i.e. herceptin, but reversible).

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10
Q

Please refer to page 10 diagram for Cancer Chemo part 2.

A

ok

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11
Q

Please refer to page 11 diagram for Gleevec (lmatinib)

A
  • fusion of BCR-ABL has increased tyrosine kinase activity
  • BCR-ABL protein transform hematopoietic cells so growth and survival becomes independent of cytokines
  • protects hematopoietic cells from programmed cell death (apoptosis)

Protein is the functional drivers of cancer
Activation of the BCR-ABL protein - leukemia after
Downstream fx

imatinib specifically inhibits this protein

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12
Q

what are the 3 types of protein kinase inhibitors and their treatment usage?

Proto-onco genes are usually kinases
Kinase - protein with catalytic domain and can bind to many proteins to phosphorylate them - important for signalling cascade

A

• Imatinib
– A conceptual breakthrough in targeted therapy. It had transformed the prognosis of patients with CML. It also inhibits PDGFR (platelet-derived growth factor receptor) (off target). BCR-ABL

• Erlotinib
– Potent inhibitor of EGFR (epidermal growth factor receptor) and is used to treat non-small cell lung cancer and pancreatic cancer.
- very selective

• Sorafenib
– Pan-kinase inhibitor that non-specifically targets several tyrosine-kinase receptors (VEGFR, PDGFR, Raf family kinases).

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13
Q

List the 6 types of EGFR inhibitors:

ending?

A
  1. Erlotinib (Lung)
  2. Gefitinib(Lung)
  3. Afatinib (Lung)
  4. Osimertinib (Lung)
  5. Cetuximab (Colon)
  6. Panitumumab (Colon)

nib for tyrosine kinase inhibitors

FYI

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14
Q

What are the side effects using protein kinase inhibitors

A
  • GI symptoms (pain, diarrhoea, nausea)
  • Fatigue
  • Headaches
  • Cardiotoxicity (rare), receptors present on cardiomyocytes
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15
Q

What are the 4 other cytotoxics?

don’t need to know

A
  • Hydroxyurea (Leukemia)
  • Bleomycin (Lymphoma)
  • Asparaginase (Leukemia)
  • Tamoxifen (Breast)
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16
Q 
See slide 16
See slide 17
See slide 18
See slide 19
See slide 20 - ranking prob of having driver mutation
See slide 21
See slide 22
A

Hyperactivated receptors signal the kinase (RAS)
RAS activates otehr kinase mutated in cancer (BRAF)
Superactivates MEK kinase
Superactivates ERK by phosphorylation

BEST DRUG - ideal target is mutated BRAF

Some cancers have no mutation
Specific signalling that induce proliferation in hyperactive pathway

17
Q

Resistance to Chemotherapy may result from either ____ or ____, with the emergence of a clone of cells that are less susceptible or resistant to the drug and consequently have a selective advantage over the sensitive cells.

What are the consequences when Resistance to Chemotherapy happen?

A

Later - there was a relapse
Mutation of cancer (mutation driving mutation)
Resistance

Cytotoxic drugs may induce mutation

– adaption of the tumour cells
– mutation

– Decreased accumulation of cytotoxic cells (i.e. P-
glycoprotein, expels drugs (foreign chemicals) from
the cell).
– Decreased uptake by the cells
– Insufficient activation of the drug
– Genetic resistance (SNPs)
– Rapid repair or downstream evasion of the drug
target

18
Q

What are the benefits of combination therapies?

A

• Treatment with combinations of anticancer agents
increases the cytotoxicity against cancer cells,
without necessarily increasing the general toxicity.
– For example, methotrexate, which mainly has
myelosuppressive toxicity, may be used in a
regimen with vincristine, which has mainly
neurotoxicity. The few drugs we possess with low
myelotoxicity, such as cisplatin and bleomycin, are
good candidates for combination regimens.
Can counteract AE with combo therapies

• Treatment with combination drugs also decreases the
possibility of the development of resistance to
individual agents.

• Combination therapies may also be beneficial in
decreasing the overall dose of certain cancer agents
that are known to have strong cyotoxicity (i.e.
doxorubicin).

19
Q

what are more selective than cytotoxic chemicals?

A

monoclonal and protein kinase inhibitor

233 FINAL (15 decks)

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