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Heme/ Lymph > Antineoplastic Agents Part II: The drugs themselves > Flashcards

Antineoplastic Agents Part II: The drugs themselves Flashcards

1
Q

places where cell cycle-specific drugs act

A

mitotic inhibitors- M
Bleomycin, etoposide, and teniposide: G2
DNA synthesis inhibitors- S

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2
Q

When do cell cycle-nonspecific drugs act?

A

G0
all DNA alkylating drugs and most DNA intercalating drugs
(does not allow unwinding of DNA for transcription, etc.)

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3
Q

Five major types of alkylating agents:

A 
Nitrogen mustards (cyclophosphamide)
Nitrosoureas (carmustine)
Alkyl sulfonates (busulfan)
Methylhydrazine derivatives (procarbazine)
Triazines (dacarbazine)

Also included are platinum compounds (cisplatin)

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4
Q

most widely used alkylating agent?

A

The nitrogen mustard cyclophosphamide is the most widely used alkylating agent and one of the most emetogenic agents
Cell cycle nonspecific

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5
Q

Alkylating Agents: Mechanism of Action

A

Alkylating agents form covalent linkages with DNA

Bifunctional alkyllating agents can cause intrastrand linking and cross-linking

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6
Q

Biotransformation of Cyclophosphamide

A

prodrug that breaks down to hydroxycyclophosphamide and aldophosphamide via ***CYP2B (active compounds)

Later: Acrolein causes hemorrhagic cystitis

***Mesna inactivates acrolein and is used for prophylaxis of chemotherapy-induced cystitis

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7
Q

Alkylating Agents: Toxicities

A

Cyclophosphamide – hemorrhagic cystitis
Cisplatin – renal tubular damage, ototoxicity
Busulfan – pulmonary fibrosis

Systemic toxicities are dose related
Direct vesicant [blistering skin] effects and tissue damage at site of injection (oral administration is of great clinical benefit)
Many alkylating agents produce acute toxicity, such as nausea and vomiting within 30-60 minutes (pretreat with serotonin antagonist)
Delayed toxicities include the common side effects of antineoplastics: bone marrow depression with leukopenia, thrombocytopenia, nephrotoxicity, alopecia, mucosal ulceration, intestinal denudation

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8
Q

Drug List: Antimetabolites

A

Folic acid analogs:
Methotrexate (MTX)

Pyrimidine analogs: Fluuorouracil

Purine analogs: Mercaptopurine

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9
Q

Three major types of antimetabolites:

and mech of action

A 
Folic acid analogs (methotrexate)
Pyrimidine analogs (5-Fluorouracil)
Purine analogs (6-mercaptopurine)

Mechanism of Action:
Structural analogs to compounds necessary for cell proliferation
Block or subvert pathways that are involved in, or lead to, cell replication (nucleotide and nucleic acid synthesis)

Cell cycle specific (S phase)

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10
Q

Methotrexate: Mechanism of Action

A

Inhibits dihydrofolate reductase (DHFR)

Indications:
Cancer
Rheumatoid arthritis
Psoriasis

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11
Q

Methotrexate & Leucovorin Rescue

A

Leucovorin: reduced folate can bypass DHFR

Used to rescue normal cells from high-dose MTX

Antidote for accidental MTX overdose

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12
Q

Pyrimidine Structural Analogs- prototype and MOA

A

5-Fluorouracil (5-FU)
Prodrug

Active compound (FdUMP) covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate

Active compounds (FdUTP and FUTP) are incorporated into both DNA and RNA, respectively

Leucovorin can’t rescue

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13
Q

Purine Structural Analogs- prototype and MoA

A

Prototype: 6-Mercaptopurine (6-MP)
Prodrug

Mechanisms of Action
Inhibition of several enzymes of de novo purine nucleotide synthesis
Incorporates into DNA and RNA

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14
Q

Drug Interaction: 6-MP & Allopurinol

A

Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase (first pass effect)

Allopurinol, a xanthine oxidase inhibitor, is often used as supportive care in the treatment of acute leukemias to prevent hyperuricemia due to tumor cell lysis

Simultaneous administration of allopurinol and oral 6-MP results in increased levels of 6-MP and increased toxicity

Reduce oral 6-MP dose by 50-75%; IV dose unaffected

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15
Q

Antimetabolites: Pharmacodynamics

A

Cell cycle specific (S-phase)

Relatively little acute toxicity after an initial dose

Oral, intravenous, and intrathecal (methotrexate) are common routes of administration

Common toxicities include diarrhea, myelosuppression, nausea, vomiting, immunosuppression, thrombocytopenia, leukopenia, hepatotoxicity

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16
Q

Vinca Alkaloids: Mechanism of Action

A

Prototypes: vinblastine and vincristine

Bind to β-tubulin and inhibit microtubule assembly
Cell cycle specific mitosis inhibition (M-phase)

“Vin-hibit microtubules”

17
Q

Vinca Alkaloids Adverse Effects

A

Prototypes: vinblastine and vincristine

Adverse Effects
Alopecia
Myelosuppression (vinblastine > vincristine)
Vincristine exhibits neurotoxicity (numbness and tingling of the extremities, loss of deep tendon reflexes, motor weakness, autonomic dysfunction has also been observed)

Alkaloid Assembly (AA)

18
Q

Taxanes: Mechanism of Action

A

Prototype: paclitaxel

Bind to β-tubulin and stabilize microtubule assembly [need to be able to breakdown and put togehter the microtubules all the time]

Cell cycle specific mitosis inhibition (M-phase)

“Daxane Disassembly”

19
Q

Taxanes

A

Prototypes: paclitaxel and docetaxel

Adverse Effects
Paclitaxel
Hypersensitivity reactions in hands and toes, change in taste

Docetaxel
Greater cellular uptake; retained intracellularly longer than paclitaxel permitting smaller dose, which reduces AEs
Hypersensitivity, neutropenia, alopecia

Indicated for treatment of several solid tumors

20
Q

Topoisomerase Inhibitors- 2 types

A

Type I Topoisomerases cut one strand of double-stranded DNA, relax the strand, and reanneal the strand

Type II Topoisomerases cut both strands of double-stranded DNA simultaneously to wind and unwind DNA supercoils
Inhibitors:
Epipodophyllotoxins (etoposide) 
Anthracycline antibiotics (doxorubicin)

Cell cycle specific (primarily S phase, also G1 and G2)
Except anthracyclines, which are CCNA

21
Q

Four major antineoplastic antibiotics:

A

Anthracyclines (doxorubicin and others)
Bleomycin
Dactinomycin
Mitomycin

Effects are mainly on DNA
All of the anticancer antibiotics currently in use are products of various species of the bacterial genus Streptomyces

22
Q

Anthracyclines: Pharmacodynamics

A

Prototype: doxorubicin

Mechanisms of Action
Inhibit topoisomerase II
Intercalate DNA***therefore cell cycle non-specific
Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks

Cell cycle nonspecific (but cycling cells are most susceptible)

Free radicals are linked to significant cardiotoxicity
Cumulative cardiac damage can lead to arrhythmias and heart failure
[track the doses over a pt’s lifetime]

23
Q

Antitumor Antibiotics: Pharmacodynamics

A

Bleomycin
MOA: Free radicals cause single- and double-strand DNA breaks
Cell cycle specific (G2 arrest)
Causes minimal myelosuppression – useful in combination
Can cause significant pulmonary toxicity (5-10%, usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles)

Dactinomycin
MOA: Intercalates DNA
Cell cycle nonspecific

“Dact-ercalate”

Mitomycin
MOAs: metabolized to an alkylating agent; forms oxygen free radicals
Cell cycle nonspecific

“Mit-oxygen”

24
Q

Antineoplastic Enzymes- MoA, AEs, Indication

A

Prototype: L-asparaginase

MOA: hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
Cell cycle specific (G1)

Adverse Effects:
Acute hypersensitivity reaction
Delayed toxicities include an increased risk of clotting and bleeding, pancreatitis, and CNS toxicity including lethargy, confusion, hallucinations, and coma

Indication: Targeted therapy for acute lymphoblastic leukemia (ALL)
ALL tumor cells lack the enzyme asparagine synthetase and thus require an exogenous source of L-asparagine

25
Q

Tyrosine Kinases and Cancer

A

When mutated, overexpressed, or structurally altered, tyrosine kinases can become potent oncoproteins

Abnormal activation of tyrosine kinases has been found in many human neoplasms

Aberrant tyrosine kinase activity can occur in receptor tyrosine kinases or cytoplasmic kinases

Attractive targets for cancer therapy

** Intracellular (nibs) vs. extracellular (mabs)

26
Q

What we need to associate Imatinib with

A

Bcr-Abl, CML

The BCR-ABL fusion protein results from the t(9:22) [Philadelphia chormosome] translocation and is found in 95% of patients with CML

Imatinib is a small molecule inhibitor of the ABL tyrosine kinase and has been hailed as a conceptual breakthrough in targeted chemotherapy

Imatinib can also inhibit the RTKs PDGFR and c-KIT

27
Q

Erlotinib and Gefitinib MOA and AE

A

MOA: Inhibit Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase
Preferred single-agent first-line therapy for NSCLC patients with somatic activating EGFR mutations
Produce dermatologic toxicities

28
Q

Inhibtion of HER2/neu

A

The epidermal growth factor receptor HER2/neu is expressed on the cell surface of 25-30% breast cancers

Activation of HER2/neu induces differentiation, growth, and proliferation

Trastuzumab and lapatinib target HER2/neu

Cardiovascular complications occur with trastuzumab (decreased LVEF, HF); less CV complications with lapatinib

29
Q

Bevacizumab- stuff

A

Antigen: VEGF
Cancer: Colorectal, lung
Antigen function: angiogenesis

“Bev-Vegf”

30
Q

Cetuximab stuff

A

Antigen: EGFR (ErbB1)
Cancer: Colorectal, lung, pancreatic, breast
Antigen function: tyrosine kinase

31
Q

Rituximab stuff

A

Antigen: CD20
Cancer: Non-hodgkin’s lymphoma
Antigen function: proliferation, differentiation

32
Q

Trastuzumab stuff

A

antigen: HER2/ neu
Cancer: Breast
Antigen function: tyrosine kinase

33
Q

Differentiating Agents

A

The t(15;17) translocation creates the fusion protein PML-RARα, which inhibits granulocytic maturation in APL

Tretinoin (all-trans-retinoic acid, ATRA) binds to the PML-RARα fusion protein and antagonizes the inhibitory effect on the transcription of target genes

Within 1-2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die

One of the most successful uses of targeted therapy in cancer

Vitamin A toxicity and retinoic acid syndrome are common adverse effects

34
Q

Biological Response Modifiers

A

Agents that stimulate or suppress the immune system to help the body fight cancer

Interferons (interferon-α2a and -α2b)
MOA: Inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, and augment cytotoxicity of lymphocytes for target cells
Adverse effects: bone marrow depression, neutropenia, anemia, renal toxicity, edema, arrhythmias, and flu-like symptoms

Interleukin-2
MOA: Increases cytotoxic killing by T cells and NK cells
Major toxicity is capillary leak syndrome

Heme/ Lymph (15 decks)

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