Antineoplastic Agents Part II: The drugs themselves Flashcards
places where cell cycle-specific drugs act
mitotic inhibitors- M
Bleomycin, etoposide, and teniposide: G2
DNA synthesis inhibitors- S
When do cell cycle-nonspecific drugs act?
G0
all DNA alkylating drugs and most DNA intercalating drugs
(does not allow unwinding of DNA for transcription, etc.)
Five major types of alkylating agents:
Nitrogen mustards (cyclophosphamide) Nitrosoureas (carmustine) Alkyl sulfonates (busulfan) Methylhydrazine derivatives (procarbazine) Triazines (dacarbazine)
Also included are platinum compounds (cisplatin)
most widely used alkylating agent?
The nitrogen mustard cyclophosphamide is the most widely used alkylating agent and one of the most emetogenic agents
Cell cycle nonspecific
Alkylating Agents: Mechanism of Action
Alkylating agents form covalent linkages with DNA
Bifunctional alkyllating agents can cause intrastrand linking and cross-linking
Biotransformation of Cyclophosphamide
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
Alkylating Agents: Toxicities
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
Drug List: Antimetabolites
Folic acid analogs:
Methotrexate (MTX)
Pyrimidine analogs: Fluuorouracil
Purine analogs: Mercaptopurine
Three major types of antimetabolites:
and mech of action
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)
Methotrexate: Mechanism of Action
Inhibits dihydrofolate reductase (DHFR)
Indications:
Cancer
Rheumatoid arthritis
Psoriasis
Methotrexate & Leucovorin Rescue
Leucovorin: reduced folate can bypass DHFR
Used to rescue normal cells from high-dose MTX
Antidote for accidental MTX overdose
Pyrimidine Structural Analogs- prototype and MOA
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
Purine Structural Analogs- prototype and MoA
Prototype: 6-Mercaptopurine (6-MP)
Prodrug
Mechanisms of Action
Inhibition of several enzymes of de novo purine nucleotide synthesis
Incorporates into DNA and RNA
Drug Interaction: 6-MP & Allopurinol
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
Antimetabolites: Pharmacodynamics
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
Vinca Alkaloids: Mechanism of Action
Prototypes: vinblastine and vincristine
Bind to β-tubulin and inhibit microtubule assembly
Cell cycle specific mitosis inhibition (M-phase)
“Vin-hibit microtubules”
Vinca Alkaloids Adverse Effects
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)
Taxanes: Mechanism of Action
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”
Taxanes
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
Topoisomerase Inhibitors- 2 types
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
Four major antineoplastic antibiotics:
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
Anthracyclines: Pharmacodynamics
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]
Antitumor Antibiotics: Pharmacodynamics
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”
Antineoplastic Enzymes- MoA, AEs, Indication
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
Tyrosine Kinases and Cancer
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)
What we need to associate Imatinib with
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
Erlotinib and Gefitinib MOA and AE
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
Inhibtion of HER2/neu
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
Bevacizumab- stuff
Antigen: VEGF
Cancer: Colorectal, lung
Antigen function: angiogenesis
“Bev-Vegf”
Cetuximab stuff
Antigen: EGFR (ErbB1)
Cancer: Colorectal, lung, pancreatic, breast
Antigen function: tyrosine kinase
Rituximab stuff
Antigen: CD20
Cancer: Non-hodgkin’s lymphoma
Antigen function: proliferation, differentiation
Trastuzumab stuff
antigen: HER2/ neu
Cancer: Breast
Antigen function: tyrosine kinase
Differentiating Agents
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
Biological Response Modifiers
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
