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pipi&pi3 > Antineoplastic Drugs > Flashcards

Antineoplastic Drugs Flashcards

1
Q

What are the hallmarks of cancer?

A

1) Enhanced growth signals
2) Insensitivity to antigrowth signals
3) Tissue invasion and metastasis
4) Limitless replicative potential
5) Chronic inflammation
6) Sustained angiogenesis
7) Evading apoptosis

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2
Q

What is primary resistance to chemotherapy?

A

When cancer does not respond to standard chemo from the FIRST exposure

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3
Q

What is acquired resistance to chemotherapy?

A

When tumor initially responds and then becomes resistant?

Causes:
- Mutation develops pathways independent of those blocked by chemotherapy
- Cells develop mechanisms that inactivate the chemotherapeutic agent
- Cells learn to repair DNA and other protein damages

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4
Q

What are the disadvantages of combination therapy?

A
  • Multiple toxicities
  • Holding doses due to toxicity will reduce effectiveness
  • Complicated to administer
  • Expensive
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5
Q

What are the basic concepts of cancer and chemotherapy?

A

1) Cells within the tumor consists of 3 subpopulations
- Non-dividing terminally differentiated cells
- Continually proliferating cells
- Resting cells

2) Tumor growth depends on:
- Tumor doubling time
- Rate of cell loss
~ Due to immune system, tumor shedding, apoptosis and necrosis
- Growth fraction
~ Actively growing fraction of tumor

3) Tumor becomes detectable when there is at least 10^9 cells

4) Skipper-Schabel model of tumor growth
- 1 leukemic cell can be lethal to the host
- % of cells killed at any given dose is constant
~ Phenomenon of constant fractional drug kill regardless of population size
~ Multiple rounds needed to fully kill all
- % of cells killed is directly proportional to the dose level

5) Gompertzian model of tumor growth
- Growth rate of tumor cells decreases with time
- Response to chemo is during rapid growth phase

6) Goldie-Coldman hypothesis
- A fraction of tumor cells will develop resistance after treatment
- Clone will continue to grow even if px responds
- Alternating combis of chemo agents early on prevents development of treatment resistant clones

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6
Q

What are the side effects of therapy?

A
  • Affects cells with high growth fraction
    ~ Even normal cells
    ~ eg Bone marrow, hair follicles, GI mucosa, skin
  • Decreased WBC, RBC, PLT (myelosuppression)
  • Alopecia
  • Mucositis
    ~ Inflammation and ulceration of mucous membranes lining the digestive tract
  • N/V
    ~ Due to stimulation of the vomiting centre in the CNS and nerves in the GI tract
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7
Q

What are the stages of the cell cycle?

A

1) Mitotic phase
- PMAT

2) G1 phase
- Duplicates organelles

3) S phase
- Replicates DNA

4) G2 phase
- Synthesized enzymes and proteins
- Replication of centrosomes completed

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8
Q

What are the cell cycle non-specific agents?

A

1) Alkylating agents
- Nitrogen mustards
~ CYCLCOPHOSPHAMIDE
- Ethylenimines
~ THIOTEPA
- Alkyl sulfonates
~ BUSULFAN
- Nitrosureas
~ CARMUSTINE

2) Antibiotics
- Anthracyclines
~ DOXORUBICIN
~ DAUNORUBICIN
- DACTINOMYCIN/actinomycin D

3) Cisplatin

4) Nitrosureas

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9
Q

What are the cell cycle-specific agents?

A

1) Antimetabolites
- Folic acid analogs
~ METHOTREXATE
- Pyrimidine analogs
~ FLUOROURACIL
- Purine analogs
~ Mercaptoguanine

2) Plant alkaloids
- Vinca alkaloids
~ VINBLASTINE
- Podophyllotoxins
~ ELOPOSIDE
- Taxanes
~ PACLITAXEL
- Camptothecins
~ Topotecan

3) Bleomycin

4) Podophyllin alkaloids

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10
Q

What is the MOA of alkylating agents (non cell cycle-specific)?

A
  • Binds to DNA to break it
  • Miscoding through abnormal base-pairing
    ~ Pairs guanine with thymine instead of cytosine
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11
Q

What are the major toxicities of alkylating agents (non cell cycle-specific)?

A
  • Myelosuppression
  • Alopecia
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12
Q

What are the MOA of nitrosoureas?

A
  • Alkylation of DNA & carbamylation of lysine residues on proteins
  • Can cross the blood brain barrier due to high lipid solubility
    ~ Useful in treating malignancies of the CNS
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13
Q

What is the MOA of anthracycline Abx (non cell-cycle specific)?

A

1) Prevents replication of rapidly-growing cancer cells
- by inhibiting DNA and RNA synthesis

2) Blocks DNA transcription and replication
- by inhibiting topoisomerase II enzyme
- relaxes supercoiled DNA

3) Creates free oxygen radicals that damage the DNA and cell membranes

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14
Q

What are the side effects of anthracycline Abx?

A
  • cardiotoxicity due to free radical production
  • alopecia
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15
Q

What is the MOA of Dactinomycin?

A
  • Intercalates in DNA minor grooves between adjacent GC pairs
  • Prevents elongation by RNA polymerase
  • Inhibits transcription
  • Inhibits topoisomerase II
  • Cytotoxic
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16
Q

How is folate important in DNA/RNA synthesis?

A
  • Provides single carbon group for precursors for synthesis
  • To function as a cofactor, folate must be reduced by DHFR to THF
17
Q

What is the MOA of methotrexate/MTX (folic acid analogue, cell-cycle specific)?

A
  • Competitively inhibits dihydrofolate reductase (DHFR)
    ~ Enzyme which catalyses the formation of tetrahydrofolate (THF) from dihydrofolate (DHF)
    ~ tf no THF formed -> intracellular folate deficiency and accumulation of toxic DHF
  • Reactions for purine synthesis cease
    ~ Interrupts DNA and RNA synthesis
  • Often used for breast cancer etc
18
Q

What is MTX toxicity?

A

1) Bone marrow suppression
- Rescue with leucovorin / folinic acid

2) Nephrotoxic
- Give sodium bicarbonate to alkalinize the urine

19
Q

What is the MOA of 5-Fluorouracil (pyrimidine antagonists, cell cycle-specific)?

A
  • Inhibits thymidylate synthase
    ~ Depletion of thymidylate
    ~ Inhibits DNA synthesis
    ~ Fraudulent RNA formation causes cytotoxicity
20
Q

What are the major toxicities of 5-florouracil?

A
  • Myelosuppression
  • Mucositis
  • Dermatitis
  • Diarrhea
  • Cardiac toxicity
21
Q

What is Gemcitabine (antimetabolite, cell cycle specific) used for?

A
  • Inhibits DNA replication and repair
    ~ Competes with dCTP for incorporation into DNA strands
    ~ Characteristics of apoptosis
    ~ More difficult to remove from DNA strands so hard to repair
  • More used for pancreatic cancer
22
Q

What are the major toxicities of gemcitabine?

A
  • Neutropenia
  • N/V
  • Fever
23
Q

What is the MOA of vinca alkaloids (plant alkaloids, cell cycle specific)?

A
  • Inhibits microtubules assembly
    ~ Mitotic cell arrest in metaphase
  • VINBLASTINE
  • Usually used for lymphomas and leukemias
24
Q

What are the major toxicities of vinca alkaloids?

A
  • Alopecia
  • Hyponatremia
  • Myelosuppression
25
Q

What is the MOA of podophyllotoxins (plant alkaloids, cell cycle specific)?

A
  • Blocks cells in the late S-G2 phase of the cell cycle
    ~ Inhibition of topoisomerase
  • DNA damage
    ~ Through formation of a complex of drug, DNA and enzyme
26
Q

What are the major toxicities of podophyllotoxins?

A
  • Myelosuppression
  • Mucositis
  • GI tract toxicities
27
Q

What is the MOA of taxanes (cell cycle specific)?

A
  • Interferes with normal function of microtubule breakdown
    ~ Hyperstabilizes microtubule structure (cannot disassemble)
28
Q

What are the spindle poisons?

A
  • Vinca alkaloids (prevent assembly of spindles during mitosis)
  • Taxanes (prevent disassembly of spindles)
  • Mostly used for lung, ovarian, breast, head and neck cancers
29
Q

What are the major toxicities of taxanes?

A
  • Myelosuppression
  • Alopecia
  • Neuropathy
  • Allergies
30
Q

What are molecular targeted therapies?

A
  • Block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression

Advantages:
- ^ therapeutic index
- Less harmful to normal cells
- ^ drug distribution to tumors using Ab-drug conjugates (ADC)

31
Q

What are some examples of molecular targeted therapies?

A

1) Monoclonal Abx
- Cituximab (anti-EGFR monoclonal Ab)
~ Binds to extracellular domain of EGFR and blocks its downstream signalling
- Herceptin (monoclonal Ab)
~ Binds to extracellular domain of HER2 receptor
~ Ab-dependent cell-mediated cytotoxicity

2) Small molecule inhibitors
- Erlotinib/Geftinib (tyrosine kinase inhibitors)
~ Blocks EGFR signalling by competitively binding to ATP pockets
- Bortezomib
~ Usually used for multiple myeloma (Abnormal expansion of plasma cells in bone marrow)

32
Q

What is acute lymphocytic leukemia (ALL) and what are the s/s?

A
  • Cancer of the blood and bone marrow

s/s:
- Bleeding gums, nosebleeds
- Bone pain
- Lumps in swollen ymph nodes
- Fever
- Pale skin
- SOB
- Fatique
- Frequent infx

33
Q

What are the treatment phases for ALL?

A

1) Induction
- Kill most of the leukemia cells
- Restore normal blood cell production
- VINCRISTINE, DAUNORUBICIN

2) Consolidation
- Destroy any remaining leukemia, eg in brain or spinal cord
- VINCRISTINE, DAUNORUBICIN, Cyclophosphamide, Etoposide

3) Maintenance
- Prevents leukemia cells from re-growing
- Much lower doses, over a long period of time

in Targeted therapies:
- Leukemia cells have Philadelphia chromosome -> new gene BCR-ABL
~ Has a protein that allows cells to grow
- Tyrosine kinase inhibitors (TKIs) attack problem
- IMATINIB MESYLATE, PONATINIB

34
Q

What are the adverse effects of treatment for ALL?

A
  • N/V
  • Diarrhea
  • Edema
  • Swelling in legs, or around the eyes
  • Usually not as severe, and can be managed
35
Q

What is Hodgkin’s lymphoma (HL)?

A
  • Malignant cells are termed lymphocyte predominant (LP) cells
    ~ Positive fro CD20 and lack CD30
36
Q

What is the treatment for HL?

A
  • Chemo + radio
  • 2nd-line
    ~ High dose chemo + autologous stem cell transplantation (ASCT)
  • Targeted therapies
    ~ CD30 Ab-drug conjugate + PD-1 inhibitors
    ~ BRENTUXIMAB VEDOTIN + NIVOLUMAB, PEMBROLIZUMAB

pipi&pi3 (22 decks)

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