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PPNP 3 > Oncology Drugs > Flashcards

Oncology Drugs Flashcards

1
Q

Skipper-Schabel model of tumour growth

A
  1. To completely cure cancer, it is necessary to kill every cancer cell in the host, regardless of the number, anatomic distribution or metabolic heterogeneity
  2. Chemotherapy kills cancer cells by a fixed percentage, not a fixed number –> constant fractional (or percentage) drug kill of a cell
    population, regardless of the population size
  3. Percentage of cancer cells killed by single-dose treatment is directly proportional to the dose level
    of the drug (i.e., the higher the dose, the higher the percentage cell kill)
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2
Q

Gompertzian Model of Tumor Growth

A
  1. Growth–Growth rate of tumor cells decreases with time
  2. Response to chemotherapy is during rapid growth phase.
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3
Q

Goldie-Coldman Hypothesis

A
  1. A fraction of tumor cells will develop resistance after treatment.
  2. This clone will continue to grow even though the patient
    appears to respond.
  3. Alternating combinations of chemotherapy agents early in
    treatment is necessary to prevent development resistant clones.
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4
Q

Classification of chemotherapeutic agents

A

Classified based on their actions related to the cell cycle

  1. Cell cycle SPECIFIC agents
    - antimetabolite
    - plant alkaloids
  2. Cell cycle NON-SPECIFIC agents
    - alkylating agents
    - antibiotics
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5
Q

What is cell cycle specific & cell cycle non-specfic?

A

Cell cycle non-specific: can kill cancer cells regardless of the phase of the cell cycle.

Cell cycle specific: target cells that are actively dividing and work best in a specific phase of the cell cycle.

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6
Q

MOA of alkylating agents (cell cycle non-specific)

A

In general: Bind to DNA, causing breaks

  • Alkylate with DNA, result in miscoding through abnormal base-pairing or depurination —> result in strand breakage
  • Cross linking of DNA or ring cleavage may also occur

e.g. Busulfan (for chronic myeloid leukemia), cyclophosphamide , melphalan

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7
Q

Side effects of alkylating agents

A

Major toxicity:
- myelosuppression
- alopecia

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8
Q

MOA of anthracycline antibiotics (cell cycle non-specific)

A
  • Inhibits DNA and RNA synthesis by intercalating between base pairs of the
    DNA/RNA strand –> prevent replication of rapidly-growing cancer cells
  • Inhibits topoisomerase II enzyme –> prevent relaxing of supercoiled DNA –> blocks DNA transcription and replication
  • Creates free oxygen radicals that damage DNA and cell membranes

e.g. Doxorubicin, Daunorubicin (“RUBICIN”)

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9
Q

Side effects of anthracycline antibiotics

A

CARDIOTOXICITY due to free radical production

Alopecia

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10
Q

Sub classes of Plant Alkaloids (cell specific agents)

A
  1. VINCA ALKALOIDS
    e.g. Vinblastine
  2. Podophyllotoxins
    e.g. Etoposide
  3. Camptothecins
    e.g. Topotecan
  4. TAXANES
    e.g. Paclitaxel
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11
Q

MOA of Vinca Alkaloids (e.g. Vinblastine)

A

Target: Microtubular protein (tubulin) in the cancer cells, acts during M phase (Cell cycle SPECIFIC)

Action:
- Bind to tubulin in a dimeric form (a pair of proteins).
- Prevent the assembly of new microtubules.
- Cause existing microtubules to break down (depolymerize).

Effect:
- Stops the cell cycle at the M phase (mitotic arrest).
- Dissolves the mitotic spindle (structure required for cell division)
- Prevents proper chromosome segregation during mitosis

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12
Q

MOA of Taxanes (e.g. Paclitaxel)

A

Action:
- Stops microtubules from breaking down (hyperstabilizes them).
-Binds to the β-subunit of tubulin.
- Prevents microtubules from disassembling.

Effect:
- Disrupts the normal shortening and lengthening (dynamic instability) of microtubules.
- Blocks their ability to transport cellular components, affecting cell function.

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13
Q

Vinca alkaloids & Taxanes comparison

A
  • Taxanes STABILIZE MICROTUBULES (interferes with disassembly of microtubules) whereas
    Vinca alkaloids BLOCK MICROTUBULE ASSEMBLY.
  • Both are called SPINDLE POISONS or mitosis inhibitors.
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14
Q

Side effects of taxanes

A

Myelosuppression
Alopecia
Neuropathy
Allergies

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15
Q

Sub classes of Antimetabolites (cell cycle specific agents)

A
  1. FOLIC ACID ANALOGS
    e.g. Methotrexate
  2. Purine Analogs
    e.g. Mercaptoguanine
  3. PYRIMIDINE ANALOGS
    e.g. Fluorouracil, Gemcitabine

Note: All primarily target S phase of cell cycle (CELL CYCLE SPECIFIC)

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16
Q

MOA of Antimetabolites - Folic Acid Analog - Methotrexate (MTX)

A
  • FOLIC ACID ANALOG (mimics folic acid but prevents its normal function, which is to synthesise DNA precursors –> inhibits DNA replication)

-MTX COMPETITIVELY INHIBITS DIHYDROFOLATE REDUCTASE (DHFR), an enzyme necessary for converting folic acid into its active form, tetrahydrofolate (THF)

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17
Q

Therapeutic uses of methotrexate (MTX)

A
  • PSORIASIS
  • RHEUMATOID ARTHRITIS
  • ACUTE LYMPHOBLASTIC LEUKEMIA
  • meningeal leukemia
  • choriocarcinoma
  • osteosarcoma
  • mycosis fungoides
  • Burkitt’s and non-Hodgkin’s lymphomas
  • CANCERS OF THE BREAST, head and neck, ovary, and bladder
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18
Q

Side effects of Methotrexate (MTX)

A
  1. BONE MARROW SUPPRESSION
    - rescue with LEUCOVORIN (folinic acid)
  2. NEPHROTOXIC
    - give SODIUM BICARBONATE to alkalinize the urine
19
Q

MOA of Antimetabolites - Pyrimidine Analog - Fluorouracil (5-FU)

A
  1. Inhibits Thymidylate Synthase:
    - Inhibits the enzyme needed to make thymidylate, an essential component of DNA –> Leads to DNA synthesis inhibition
  2. Incorporates into DNA –> Becomes part of the DNA structure, causing defective DNA –> Stops cancer cells from dividing and growing
  3. Inhibits RNA processing
20
Q

Therapeutic uses of Fluorouracil (5-FU)

A
  1. Metastatic carcinomas of the breast and GI tract
  2. Hepatoma
  3. Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas and oropharygeal areas
21
Q

MOA of Antimetabolites - Pyrimidine Analog - Gemcitabine

A
  1. Competes with deoxycytidine triphosphate (cCTP) for incorporation into DNA strands
  2. Prevents DNA Extension:
    Once gemcitabine is added, the DNA chain cannot grow any further, stopping cancer cell division.
22
Q

Therapeutic uses of gemcitabine

A
  • treats a variety of solid tumours
  • very effective in treatment of PANCREATIC cancer
  • small cell lung cancer
  • carcinoma of bladder, breast, kidney, ovary, head and neck
23
Q

Side effects of gemcitabine

A
  1. Neutropenia
  2. N/V
  3. Fever
24
Q

What are molecular targeted therapies? Why are they used?

A

chemotherapy agents are NOT selective (they can target the DNA, RNA and protein)

Molec targeted therapies:
- interfere specific molecues involved in tumour growth and progression
- more effective than chemotherapy as less harmful to normal cells

25
Q

Advantages of targeted therapies

A
  1. Increased THERAPEUTIC INDEX
  2. Increased DRUG SENSITIVITY for cancer cells
  3. Improved DRUG DISTRIBUTION to tumours
26
Q

Types of molecular targeted therapies

A
  1. Monoclonal antibodies (ends with “nib”, e.g. Erlotinib)
    - Bind to receptors or proteins on cancer cells, blocking signals that promote cell growth.
    - Mark cancer cells for destruction by the immune system
  2. Small molecule inhibitors
    (ends with “mab”, e.g. cetuximab)
    - Inhibit the activity of certain proteins or enzymes inside the cancer cells, which disrupts essential pathways like cell signaling, metabolism, or DNA repair.
    - Often used to target kinases (enzymes involved in cell signaling)
27
Q

Clinical application of small molecule inhibitors

A
  1. Erlotinib/gftinib for lung cancer
  2. Bortezomib for multiple myeloma
  3. Sorafenib for liver cancer
28
Q

MOA of Erlotinib and Gefitinib

A

Both used in treatment of non-small cell lung cancer

Are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

MOA:
- block activity of EGFR tyrosine kinase by binding to ATP binding site of EGFR –> block its activation and downstream signalling pathways responsible for cell proliferation and survival

29
Q

MOA of Benvacizumab

A

Monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), a protein essential for blood vessel formation in tumours

inhibiting VEGF –> blood supply to tumours reduced –> limiting its growth and ability to spread –> “starve” the tumour

30
Q

What are the targeted therapies used for Leukemia?

A
  1. Brentuximab vedotin
    MOA:
    - targets cancer cells expressing CD30, delivers a chemotherapy drug (MMAE) directly inside the cells, and causes cell death
  2. Anti-PD-1 antibodies (Nivolumab and Pembrolizumab)
    - block PD-1 on T cells, allowing them to fight cancer cells more actively by removing the immune system’s natural “brakes” or suppression
31
Q

What are the targeted therapies used for Non-Hodgkin Lymphoma (NHL)?

A

Rituximab

MOA:
binds to CD20 and eventually leads to cell lysis

32
Q

Treatment options for Non-Hodgkin Lymphoma (NHL)?

A

Alkylating agents

CHOP therapy
- Cyclophosphamide (alkylating agent)
- Doxorubicin (antibiotic)
- Vincristine (vinca alkaloid)
- Prednisone (corticosteroid)

Targeted agents like rituximab

33
Q

Limitations of molecular targeted therapy

A
  • Pathway dependence
  • Tumor heterogeneity
  • Resistance
  • Adverse effects
  • Neutralization (of biologic drugs)
34
Q

The key features of Gompertzian model include:

A. Response to chemotherapy is minimal during rapid growth phase
B. A fraction of tumor cells will develop resistance after treatment
C. The percentage of tumor cell populations killed by a given dose of a given drug is reasonably constant
D. Growth rate of tumor cells decreases with time

A

Ans: Growth rate of tumour cells decreases with time

Response to chemotherapy is MAXIMAL during rapid growth phase

Skipper-Schabel model: the third option

Gompertzian:
1. Growth–Growth rate of tumor cells decreases with time
2. Response to chemotherapy is during rapid growth phase.

35
Q

Which of the following statements with respect to chemotherapeutic agents are TRUE?

A. Chemotherapy agents are cytotoxic (that is, they kill tumor cells)
B. Chemotherapeutic agents are classified based on their ability to induce apoptosis
C. Chemotherapeutic agents have high therapeutic index
D. The majority of tumor cells have not to be killed to achieve complete remission of the tumor, and hence the application of low doses of chemotherapeutics is required
E. Chemotherapeutic agents can effectively discriminate between normal and cancer cells

A

Ans: Chemotherapy agents are cytotoxic

  1. Skipper-Schabel model: majority of tumour cells have to be killed to achieve complete remission
  2. Classified based on their action to tumor cells
  3. Have low therapeutic index
36
Q

Which of the following statements with respect to targeted therapies are TRUE?

A. Very few cancers have a single genetic mutation that is entirely responsible for their development. Such genomic plasticity and resultant cellular heterogeneity precludes success of targeted therapies
B. Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells
C. Targeted therapies are deliberately chosen or designed to interact with their target, whereas many standard chemotherapies were identified because they kill cells
D. All of above

A

Ans: All of the above

37
Q

Which 2 drug combinations are together known as spindle poisons?

A

Paclitaxel and vinblastine

Both are plant alkaloids (cell-cycle specific agents)

Paclitaxel: Taxane
Vinblastine: Vinca alkaloid

38
Q

Which of the following is true about cytotoxic antibiotics?

A. They inhibit microtubules.
B. They are mostly cell cycle specific.
C. They can directly interact with DNA.
D. They exhibit minimal side-effects.
E. None of the above.

A

Ans: They can directly interact with DNA.

Plant alkaloids (Vinblastine and paclitaxel) targets microtubules.

Cytotoxic antibiotics are cell cycle non-specific.

Cytotoxic antibiotics are CARDIOTOXIC.

Methotrexate (antimetabolite –> folic acid analog) is NEPHROTOXIC

39
Q

A 40 year-old female with neuroblastoma is being treated with combination chemotherapy, consisting of cisplatin, vincristine, and carmustine. Regarding the mechanism of action of carmustine it:

A: Inhibits thymidylate synthase
B: Intercalates between base pairs of DNA strand; inhibits the enzyme DNA topoisomerase II
C: Causes both alkylation of DNA and carbamylation of lysine residues on proteins
D: Inhibits de novo purine synthesis, cell cycle dependent

A

Ans: C. Carmustine is an alkylating agent and works by alkylating DNA, which prevents DNA replication and transcription. It also carbamylates lysine residues on proteins, which can affect protein function.

Option A: Inhibits thymidylate synthase — this is the mechanism of action of 5-fluorouracil (5-FU)

Option B: Intercalates between base pairs of DNA strand; inhibits DNA topoisomerase II — this is the mechanism of action of anthracyclines (e.g., doxorubicin), not carmustine

Option D: Inhibits de novo purine synthesis, cell cycle dependent — this is the mechanism of action of methotrexate

40
Q

A 45 year-old female with chronic myeloid leukemia is treated with imatinib. The mechanism of action of imatinib is:

A.Binds to and stabilises the G1 phase of the cell cycle
B. Inhibits the tyrosine kinase activity of the BCR-ABL fusion protein
C. Causes DNA damage by generating interstrand DNA cross-links
D. Acts as an antimetabolite that interferes with nucleotide synthesis

A

Ans: B

41
Q

A 49-year-old female with cervical cancer is undergoing treatment with bevacizumab. The mechanism of action of bevacizumab is:

A. Blocking the human epidermal growth factor receptor 2 (HER2)
B. Binding to vascular endothelial growth factor (VEGF) and inhibiting angiogenesis
C. Inducing proteasome inhibition, leading to apoptosis of cancer cells
D. Acting as a topoisomerase inhibitor, preventing DNA replication and transcription

A

Ans: B

MOA:
Monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), a protein essential for blood vessel formation in tumours

inhibiting VEGF –> blood supply to tumours reduced –> limiting its growth and ability to spread –> “starve” the tumour

42
Q

Which one of the conditions indicated below do not generally arise as a result of adverse effects of chemotherapy?

A. Alopecia
b. Mucositis
C. Cystitis
D. Cataract

A

Ans: D

43
Q

The key features of Goldie-Coldman hypothesis include:

a. A fraction of tumor cells can develop resistance after treatment with chemotherapy.
b. A single chemotherapeutic agent administered early can prevent the development of resistant clones
c. Growth rate of tumor cells is unaffected by time.
d. Response to chemotherapy is maximal during the resting phase of the cell.

A

Ans: A.

B wrong: Combination of chemotherapy is needed

Goldie coldman
1. A fraction of tumor cells will develop resistance after treatment.

  1. This clone will continue to grow even though the patient appears to respond.
  2. Alternating combinations of chemotherapy agents early in
    treatment is necessary to prevent development resistant clones.

PPNP 3 (19 decks)

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