Antineoplastic Agents Flashcards
Cyclophosphamide
Alkylating Agent
Bischloroethyl amine
Anti-Tumor, less highly reactive derivative
Alkylating activity requires activation in liver or tumor tissues
Treats autoimmunity as well
Mechlorethamine
Alkylating agent
Bischloroethyl amine
Nitrogen mustard (prototype of alkylating agents)
Analog of mustard gas
Highly Reactive DNA alkylating/damaging agent
Necrosis if given as IV administration
A part of the MOPP regiment (Hodgkin’s disease) with vincristine, procarbazine, and prednisone
Nitrosoureas
Alkylating Agent
Little cross-resistance with other alkylating agents
Crosses blood-brain barrier
Useful against brain tumors
Compare with bichloroethyl amines
Procarbazine
Alkylating Agent
Metabolized to alklating and free radical (reacting) intermediate
Effective in MOPP regimen against Hodkin’s disease
Little cross-resistance with other antineoplastic agents
Leukemogenic (5-10% risk with MOPP regimen), alternative is ABVD regimen
Highly toxic
cisplatin and carboplatin
Platinum Coordination complex
Reacts with DNA causing displacement of helix/cross-linking
Blocks the DNA repair enzyme to fix the DNA damage
2 Chlorides allow cross link to occur
Cell cycle nonspecific, DNA crosslinking
May inhibit DNA biosynthesis
Useful in various combination regimens
Ovarian and testicular cancer
Clinical toxicity: NEPHROTOXIC (hydration) and ACOUSTIC NERVE DYSFUNCTION
methotrexate
Anti-tumor Antimetabolite
Folic acid analog
Dihydrofolate reductase inhibitor (DHFR)
Blocks synthesis of DNA, RNA and precursors
Accumulates in cells as Polyglutamate derivative
S phase-specific!!
Structures contains extra methyl that causes disfunction
Mechanisms of Resistance
- Amplification of DHFR gene
- DHFR gene mutation
- Decreased uptake
- Increased drug efflux
FOLINIC ACID “rescues” aids in bone marrow recovery
Leucovorin-folinic Acid Rescue
Rescues body from methotrexate toxicity by aiding in bone marrow recovery,
Cycled after methotrexate use
Fluorouracil (5-FU)
Pyrimidine Antagonist
Metabolite Fluorodeoxyuridine monophosphate (FdUMP) inhibits thymidylate synthetase– THYMINELESS DEATH
Metabolites incorporated into newly synthesized DNA and RNA
S phase-specific
capecitabine
Pyrimidine Antagonist
Oral prodrug of fluorouracil
Preferentially activated in tumor tissues (thymidine phosphorylase)
Approved for COLON CANCER and REFRACTORY BREAST CANCER
- Due to tumor cells having a high lvl of thymidine phosphorylase
Enzymes for Metabolism: - Carboxylesterase (Capecitabine-- 5-DFCR) - Cytidine Deaminase (5-DFCR---5 DFUR) - Thymidine Phosphorylase (5-DFUR--5-FU) - Dihydropyrimidine dehydrogenase
Cytarabine (cytosine arabinoside), araC
Pyrimidine Antagonist
Converted into araCMP, then to araCTP
araCTP is an inhibitor of DNA synthesis, also incorporated into DNA leading to mutations/DNA strand breaks
Metabolic activation requires Deoxycytidine kinase
Mutational loss of deoxycytidine kinase: MECHANISM of TUMOR CELL RESISTANCE
6-mercaptopurine/
Purine Antagonist
Metabolites inhibit de novo purine synthesis (masquerade as normal base)
Interfere with DNA and RNA synthesis
Fraudulent base incorporation (mismatches, strand breaks)
S-phase specific
Activated by conversion to NMPs, NTPs, via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
Down regulation of HGPRT: RESISTANCE to MEDICATION
INACTIVATED by xanthine oxidase
LOW BIOAVAILABILITY when administered with Cow’s Milk (high xanthine oxidase)
Enhanced with ALLOPURINOL, due to allopurinol inhibiting xanthine oxidase (look to lower dosage)
6-thioguanine
Purine Antagonist
Metabolites inhibit de novo purine synthesis (masquerade as normal base)
Interfere with DNA and RNA synthesis
Fraudulent base incorporation (mismatches, strand breaks)
S-phase specific
Activated by conversion to NMPs, NTPs, via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
Down regulation of HGPRT: RESISTANCE to MEDICATION
bleomycin
Anti-tumor Antibiotic
Main cytotoxic action is DNA strand Scission
PULMONARY TOXICITY (pulmonary fibrosis) at large doses
NO significant myelosuppresion (allows in combination regimen (ABVD, (doxorubicin, bleomycin, vinblastine, dacarbazine) in Hodgkin lymphoma
Natural Product: “anaphylatic” reactions, administer small test dose to check first
daunorubicin
Anti-tumor antibiotic and Topoisomerase Inhibitor
Anthracyclines
Used with broad spectrum of activity
DNA intercalation (mutagenic, carcinogenic)
DNA topoisomerase II binding, DNA scission
Irreversible cardiac toxicity at HIGH DOSES
- Heart monitoring REQUIRED
doxorubicin
Anti-tumor Antibiotic
Anthracycline
Widely used with broad spectrum of activity
DNA intercalation (mutagenic, carcinogenic)
DNA topoisomerase II binding, DNA scission)
IRREVERSIBLE CARDIAC TOXICITY at HIGH DOSES (requires heart monitoring when administered)
Part of ABVD regimen for Hodgkin and other lymphoma
paclitaxel
Mitotic Spindle Poison
Plant alkaloid (bark/leaves of Western Yew)
Enhances tubulin polymerization (blocks microtubule disassembly)
Ovarian and Advanced Breast Cancers
Blocks MT disassembly
vinblastine
Mitotic Spindle Poison
Vinca Alkaloid
Part of the ABVD regimen in Hodgkins Lymphoma (doxorubicin, Bleomycin, Vinblastine, Dacarbazine)
Cell Cycle Specific (M-phase)
Inhibitor of Microtubule (tubulin) polymerization (mitotic arrest)
Side Effects: Acute nausea, Vomiting and dose-limiting bone marrow depression
Effective against Hodkins and other lymphoma
RESISTANCE by TUBULIN GENE MUTATION (cannot bind)
MYELOBLAST SUPPRESSION!!!!! (side effects)
Vincrisitine
Mitotic Spindle Poison
Vinca Alkaloid
Arrests mitosis via binding to microtubules (tubulin)
No acute side effects and milder, non-dose-limiting bone marrow depression, significant neurotoxicity (muscle weakness)
Used for Acute Childhood Leukemia
HODKINS disease (MOPP regimen)
RESISTANCE by TUBULIN GENE MUTATION
NO MYELOSUPPRESSION
Degenerates axons
Irinotecan
Topoisomerase Inhibitor
Camptothecins
Binds to the “cleavable complex” of DNA topoisomerase I and DNA, block RELIGATION of single-strand break
Double-strand breaks OCCUR with DNA replication: S PHASE SPECIFIC
Colorectal Cancer
DOSE LIMITING TOXICITY: Severe Diarrhea
etoposide
Topoisomerase Inhibitor
Blocks TOPO II
Inhibits binding by forming TENARY COMPLEX with TOPO II
Interferes with RELIGATION of DOUBLE-STRAND BREAK
DNA Strand Scission
Resistance due to:
- MDR1 Drug Transporter
Tamoxifen
Antagonist of Hormone Action
Competitive Inhibitor: Estrogen Binding
- Selective estrogen Response Modulator (SERM)
Partial agonist of estrogen receptor
Efficacy depends on estrogen receptor isoform
Low Toxicity, Side Effects are HOT FLASHES
Employed against cancers of Estrogen Responsive Tissues, FEMALE AND MALE BREAST, Uterine ENDOMETRIUM
40% OF BREAST CANCERS are estrogen sensitive
Prophylatic tamoxifen treatment suggested as effective breast cancer prevention in high-risk women
Does not increase life span
Therapy in postmenopausal women reduces risk of bone fractures
INCREASED RISK of THROMBOSIS/EMBOLISM and Endometrial cancer associated with therapy
Raloxifene
Antagonist of Hormone Action
Estrogen Receptor Partial Agonist
SERM
Approved for treatment of breast cancer
Best cancer prevention due to limited associated risks of endometrial cancer and thrombotic events (as seen in tamoxifen)
STAR study to see the effectiveness of raloxifene and tamoxifen in breast cancer prevention, showed raloxifene had a lower risk of endometrial cancer and thrombotic
anastrozole
Antagonist of Hormone Action
Aromatase Inhibitor
Inhibits conversion of androgens to estrogen
Block estrogen production in postmenopausal women
Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production
More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer
Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women
Untoward effects: joint pain, loss of bone density
letrozole
Antagonist of Hormone Action
Aromatase Inhibitor
Inhibits conversion of androgens to estrogen
Block estrogen production in postmenopausal women
Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production
More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer
Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women
Untoward effects: joint pain, loss of bone density
exemestane
Antagonist of Hormone Action
Aromatase Inhibitor
Inhibits conversion of androgens to estrogen
Block estrogen production in postmenopausal women
Not used in premenopausal women because of compensatory gonadotropin and ovarian estrogne production
More effective than Tamoxifen in treatment of Estrogen Receptor sensitive breast cancer
Useful against tamoxifen resistance tumors (second-line therapy) in postmenopausal women
Greatly reduces risk of breast cancer (75%) in high risk POSTMENAPAUSAL WOMEN
Untoward effects: joint pain, loss of bone density
leuprolide
Antagonist of hormone action
Anti-androgen therapy
Synthetic peptide of Gonadotropin Releasing Hormone (GnRH, LHRH)
- A GnRH-R agonist
Pulsatile: Delivery elevates levels of androgens in men and women
Continuous, high dose: Lowers androgen levels in men and estrogen levels in post menopausal women
- Chemical Castration, Androgen Ablation
Effective as estrogen therapy
Effective as orchiectomy in Treatment of Prostate Cancer with fewer side effects
flutamide
Antagonist of Hormone Action
Androgen Receptor Antagonist
Ineffective alone, due to rapid androgen receptor mutation
Used in conjunction with leupromide to block effets of initial pulse of androgen levels
- Blocks associated flare of prostate cancer therapy
prednisone
Adrenocorticosteroid
Anti-inflammation
Induces apoptosis in Leukemia Cells
used in multidrug regimens for leukemia, lymphoma and myeloma
Does not cure leukemias, but useful in inducing remission in acute LYMPHOBLASTIC or underdifferentiated leukemia or childhood
Palliative Agent in other cancers (reduce inflammation and nausea)
lapatinib
EGFR (epidermal growth Factor) kinase Inhibitor
HER2 Kinase Inhibitor
Small molecule used in breast cancer clinical trials (HER2+ BC)
erlotinib
EGFR (epidermal growth factor) Kinase Inhibitor
= Protein Tyrosine Kinase
- Overexpressed/mutationally activated in various cancers
- Brain, lung, head, and neck cancer
Small molecule EGFR inhibitor that is approved for non-small cell lung cancer (NSCLC) and in clinical trials for head and neck cancers
imatinib
Bcr/Abl kinase inhibior
- Arises from a gene rearragnement/fusion in CHRONIC MYLEGENOUS LEUKEMIA
Small molecule inhibitor of ABL protein tyrosine kinase
- Also against PDGFR and kit (stem cell factor receptor) kinases
Approved for:
- CHRONIC MYELOGENOUS LEUKEMIA
- GI stromal tumors (kit)
- chronic myelomonocytic leukemia (ETV6-PDGFR fusion)
cetuximab
Chimeric/humanized antibody
Chimeric EGFR (epidermal growth factor) antibody approved for use in COLON CANCER and HEAD AND NECK CANCER
trastuzumab
Chimeric/humanized antibody
Humanized antibody
Used for REFRACTORY METASTATIC BREAST CANCER
Recognizes the cell surface antigen HER2/Neu
-DRAMATICALLY elevated in 30% breast tumors
Effective against (HER2) breast tumors
Direct tumor cell effects
Immune system-mediated effects
brentuximab vedotin
Chimeric antibody
Target CD30 of Hodgkin and non-Hodgkin lymphoma cells
IgG conjgated to Highly Toxic Mitotic Spindle Poison Vedotin, Cleavable linker
Accellerated FDA approval
Upon binding, CD30-positive tumor cells internalize brentuximab vedotin and proteolytically cleaved to release toxin
