Pharm S2015 > Anticancers > Flashcards

Anticancers Flashcards

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1
Q

Cell cycle specific agents

A
  • antimetabolites
  • bleomycin
  • microtubule inhibitors
  • epipodophyllotoxins
  • camptothecins
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2
Q

cell cycle nonspecific agents

A
  • alkylating agents
  • platinum coordination complexes
  • antitumour antibiotics
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3
Q

MULTIDRUG RESISTANCE

A
  • Mainly due to overexpression of membrane efflux pumps; P-glycoprotein is the most important efflux pump responsible for multidrug resistance.
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4
Q

TOXICITY: COMMON ADVERSE EFFECTS

A
  • Doxorubicin causes cardiotoxicity.
  • Cyclophosphamide & ifosphamide cause hemorrhagic cystitis.
  • Bleomycin causes pulmonary fibrosis.
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5
Q

MINIMIZING ADVERSE EFFECTS

A
  • Leucovorin rescues bone marrow from methotrexate.
  • Mesna reduces hemorrhagic cystitis caused by cyclophosphamide and ifosfamide.
  • Dexrazoxane reduces anthracycline-induced cardiotoxicity.
  • Filgrastim reverses neutropeniac aused by many anticancer agents.
  • Amifostine is a cytoprotective agent that reduces renal toxicity caused by cisplatin.
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6
Q

ANTIMETABOLITES

A
  • FOLATE ANALOGS
  • PURINE ANALOGS
  • PYRIMIDINE ANALOGS
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7
Q

MTX

A
  • folate analog
  • DHR inhibitor
  • Methotrexate undergoes conversion to a series of polyglutamates (MTX-PGs).
  • The process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS).
  • MTX-PGs increase the inhibitory potency of MTX for additional sites, including thymidylate synthase and enzymes of the de novo purine nucleotide biosynthetic pathway.
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8
Q

MTX - Adverse

A
  • Common: Stomatitis, mucositis, myelosuppression, alopecia, nausea, vomiting.
  • Renal Damage: Uncommon. Complication of high-dose methotrexate.
  • Hepatic fibrosis and cirrhosis.
  • Pneumonitis.
  • Neurologic Toxicities. With IT administration.
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9
Q

Leucovorin

A
  • Leucovorin is N5-formyl-THF.
  • Antidote to drugs that decrease levels of folic acid, such as methotrexate, to rescue the bone marrow.
  • Leucovorin provides the normal tissues with the reduced folate, thus circumventing the inhibition of DHFR.
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10
Q

Purine analogs

A
  • 6-MP
  • 6-Thioguanine
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11
Q

6-MP

A
  • Thiol analog of hypoxanthine.
  • Converted to thio-IMP by th esalvage pathway enzyme, HGPRT.
  • Thio-IMP inhibits the first step of the de novo purine ring biosynthesis.
  • Thio-IMP also blocks formation of AMP and GMP from IMP.
  • Also,dysfunctional RNA and DNA result from incorporation of guanylate analogs.

PK

  • metabolized by Xanthine Oxidase to yield thiouric acid
  • also metabolized by TPMT
  • If allopurinol is given to reduce hyperuricemia, dose of 6-MP must be decreased to avoid accumulation of the drug.

Uses: ALL

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12
Q

6-Thioguanine

A
  • Converted to the nucleotide, which then inhibits purine synthesis and the phosphorylation of GMP to GDP.
  • It can be incorporated into RNA and DNA.
  • Used for acute non-lymphocytic leukemias.
  • Allopurinol does not potentiate 6-TG action because very little is metabolized to thiouric acid.
  • Toxicities: same as for 6-MP.

PK

  • 6-mercaptopurine and 6-thioguanine are also metabolized by the enzyme thiopurine methyltransferase (TPMT).
  • Patients who have weak activity TPMT are at increased risk for severe toxicities such as myelosuppression.
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13
Q

Pyrimidine analogs

A
  • 5-FU
  • Capecitabine
  • Cytarabine
  • Gecitabine
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14
Q

5-FU

A
  • Carbecitabine is prodrug
  • Converted to the deoxyribonucleotide 5-FdUMP.
  • 5-FdUMP inhibits thymidylate synthase. DNA synthesis is inhibited.
  • ‘Thymineless death’ results.
  • 5-FU is also converted to 5-FUTP and incorporated into RNA, interfering with RNA processing and function.

**MOA: **Thymidylate synthase inhibition

  • Leucovorin potentiates 5-FU (but inhibits MTX)

Uses

  • 5-FU is used in the treatment of carcinomas of the breast and GI tract.
  • 5-FU can be used topically for keratoses and superficial basal-cell carcinoma.
  • 5-FU/leucovorin combination is used as chemotherapy for colorectal cancer.
  • 5-FU inhibits thymidylate synthase by forming a ternary complex involving the enzyme, the substrate (5-FdUMP), and the cofactor (N5, N10- methylene-THF).
  • **Increasing levels of N5,N10-methylene-THF potentiates the activity of 5-FU. **

Metabolism

  • 5-FU is mainly metabolized by the enzyme dihydropyrimidine dehydrogenase (DPD).
  • Deficiency of DPD is seen in up to 5% of cancer patients.
  • These patients may experience severe toxicity such as myelosuppression, neurotoxicity and life-threatening diarrhea.
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15
Q

5-FU: Adverse

A
  • Nausea, vomiting, alopecia, bone marrow depression.
  • An erythematous desquamation of the palms and soles called the “hand-foot syndrome” is seen after extended infusions.
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16
Q

Capecitabine

A
  • Fluoropyrimidine carbamate.
  • Orally available prodrug of 5-FU.
  • Capecitabine’s cytotoxic activity is the same as that of 5-FU.
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17
Q

Cytarabine (ARA-C)

A
  • Analog of deoxycytidine.
  • Sequentially phosphorylated to the trisphosphate.
  • Incorporated into DNA.
  • The incorporated residue inhibits DNA polymerase.
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18
Q

Gemcitabine

A
  • Analog of deoxycytidine.
  • Anti-metabolite -> cell cycle non-specific

**MOA: **

  • Phosphorylatedbynucleosidekinasestothe nucleoside di- and triphosphate, which inhibit DNA synthesis.
  • Inhibitionresultsfromtwoactions:
  • Inhibition of ribonucleotide reductase.
  • Incorporation of gemcitabine triphosphate into DNA. This results in chain termination.
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19
Q

ANTITUMOUR ANTIBIOTICS

A
  • Bind to DNA through intercalation between bases and block synthesis of new RNA or DNA (or both), cause DNA strand breakage, and interfere with cell replication.
  • includes anthracyclines & bleomycin
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20
Q

Anthracyclines

A
  • includes doxorubucin & daunorubicin
  • The anthracycline antibiotics are among the most important antitumor agents.
  • Doxorubicin is one of the most widely used anticancer drugs.

MOA: 4 major mechanisms:

  • Inhibition of topoisomerase II
  • Intercalation in DNA with consequent blockade of DNA & RNA synthesis and strand breakage.
  • Binding to cell membranes to alter fluidity and ion transport.
  • Generation of free radicals.
  • The free radicals are the cause of the cardiac toxicity.
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21
Q

Anthracyclines: Adverse

A
  • Myelosuppression: main toxicity.
  • Cardiotoxicity:
    • Dose-dependent, dilated cardiomyopathy associated with heart failure.
    • Due to free radicals.
    • The iron-chelating agent dexrazoxane can reduce the cardiotoxicity.
  • “Radiation recall reaction” with erythema at sites of prior radiation therapy.
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22
Q

Bleomycin

A
  • Mixture of glycopeptides.
  • Like the antracyclines, bleomycin causes breakage of DNA by oxidative processes.
  • Cell-cycle specific. Arrest cells in G2 phase.

MOA

  • A DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycin- Fe3+.
  • The liberated electrons react with O2 to form free radicals which cause strand breakage.
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23
Q

Bleomycin: Adverse

A
  • The most serious adverse reaction is pulmonary toxicity (pneumonitis, fibrosis).
  • Dose-limiting.
  • Very little myelosuppression.
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24
Q

Alkylating agents

A

includes

  • nitrogen mustards (mechlorethane, cyclophosphamide, Ifosfamide, melphalan)
  • alkyl sulfonates
  • nitrosoureas
  • triazenes
  • methylhydrazines
  • Exert cytotoxic effects via transfer of their alkyl groups to various cellular constituents.
  • Alkylation of DNA is probably what leads to cell death.
  • Alkylation of DNA can occur on a single DNA strand or on both strands through cross-linking, as most major alkylating agents are bi- functional.
  • Toxicities occur particularly in rapidly growing tissues like the bone marrow, GI tract and gonads.
  • Nausea and vomiting are common.
  • Emetic effects can be reduced with 5-HT3 receptor antagonists.
  • Alkylating agents are mutagenic and carcinogenic.
  • Cyclophosphamide is the most widely used alkylating agent.
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25
Mechlorethamine including Adverse
* Very unstable. * Solutions must be made up just prior to administration. * Powerful vesicant. Only given IV. **Adverse** * Severe nausea and vomiting. * Severe bone marrow depression. * Alopecia. * Immunosuppression. * Largely replaced by cyclophosphamide, melphalan and other more stable alkylating agents.
26
Cyclophosphamide
* Can be given orally or IV. * Prodrug. * **Activated to 4-OH-cyclophosphamide by CYP2B. ** * Broad clinical spectrum. * Essential component of many drug combinations. * Most widely used alkylating agent
27
Cyclophosphamide - Adverse
* Nausea and vomiting * Bone marrow depression * Hemorrhagic cystitis * Alopecia * Sterility * Acrolein, a metabolite of cyclophosphamide is responsible for the hemorrhagic cystitis caused by therapy with cyclophosphamide. * This can be prevented by parenteral administration of mesna, a sulfhydryl compound which reacts with acrolein in the bladder.
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IFOSFAMIDE including Adverse
* Analog of cyclophosphamide. * Activated by hydroxylation in the liver by CYP3A4 **Adverse** * Similar toxicity profile to cyclophosphamide, but causes greater platelet suppression, neurotoxicity, and urinary tract toxicity. * Adequate hydration and administration of mesna permit its use.
29
Melphalan
Primarily used to treat multiple myeloma.
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Alkyl sulfonate
BUSULFAN * Mainly used in chronic myelogenous leukemia. * Myelosuppression is the main toxicity. * May cause pulmonary fibrosis.
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Nitrosoureas
CARMUSTINE LOMUSTINE * Very lipophilic. * **Cross the blood-brain barrier.** * Useful in treatment of brain tumours. * Nitrosoureas require biotransformation, which occurs non-enzymatically.
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TRIAZENES
DACARBAZINE * Acts as methylating agent after activation in the liver. * Given IV. * Indicated for malignant melanoma. * Also indicated for Hodgkin's disease. * Toxicity includes nausea and vomiting. * Myelosuppression is usually mild to moderate.
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PROCARBAZINE
* METHYLHYDRAZINES * Converted by liver P450 enzymes to alkylating metabolites. USES * Used in combination with mechlorethamine, vincristine and prednisone (the MOPP regimen) for the treatment of Hodgkin's disease. * Alternative regimens with less leukemogenic potential have replaced MOPP.
34
PROCARBAZINE: ADVERSE EFFECTS
* Leukopenia and thrombocytopenia. * **MAO inhibitor** * Disulfiram-like reactions. * Highly carcinogenic, mutagenic and teratogenic. * Potent immunosuppressive agent.
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PLATINUM COORDINATION COMPLEXES
* CISPLATIN * CARBOPLATIN * Broad antineoplastic activity. * Have become the foundation for treatment of **testicular cancer, ovarian cancer,** and cancers of the **head and neck, bladder, esophagus, lung and colon. ** * Inhibit DNA synthesis and binds DNA through formation of cross-links. * Given IV. **Uses** * Approved for testicular, ovarian, and bladder cancers. * Its use with vinblastine and bleomycin has been major advance in development of curative therapy for testicular cancers.
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CISPLATIN: ADVERSE EFFECTS
* Myelosuppression: mild-to-moderate. * Nausea and vomiting. * **Ototoxicity.** * Peripheral neuropathy. * Nephrotoxicity is abolished by hydration and diuresis. * **Amifostine** is a **cytoprotective** agent used to reduce the renal toxicity associated with cisplatin.
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Carboplatin - Adverse
* Less nausea, neurotoxicity, ototoxicity and nephrotoxicity than cisplatin. * Dose-limiting toxicity is myelosuppression.
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MT inhibitors
* Vinca alkaloids: vincristine & vinblastine * Taxanes: Paclitaxel & Docetaxel
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Vinca alkaloids including Adverse
* includes vincristine and vinblastine **MOA** * Vinca-tubulin and **inhibit** its ability to **polymerize into microtubules.** * This results in mitotic arrest in metaphase. * Cell division stops. Cells die by apoptosis. **Adverse** * Vincristine: **Peripheral neuropathy.** Bone marrow depression is mild. Alopecia. * Vinblastine: Myelosuppression is the dose- limiting adverse effect. Other adverse effects include alopecia and peripheral neuropathy
40
Taxanes
* including Paclitaxel & Docetaxel **MOA** * Taxanes bind to beta-tubulin subunit of microtubules and promote microtubule polymerization. * Stabilization of the microtubules in a polymerized state arrests cells in mitosis and leads to apoptosis.
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Taxanes - Adverse
PACLITAXEL * Hypersensitivity,myelosuppression,peripheral neuropathy, alopecia, etc * Hypersensitivity is reduced by premedication with dexamethasone, diphenhydramine and an H2 blocker * Abraxane is an albumin-bound form of paclitaxel which does not cause hypersensitivity, does not require premedication, and causes less myelosuppresion than the traditional paclitaxel. DOCETAXEL * Myelosuppression, peripheral neuropathy, fluid retention, alopecia, mucositis. * Pretreatment with dexamethasone is required to prevent fluid retention. * Docetaxel does not cause neuropathy as frequently as paclitaxel. * Myelosuppression is dose-limiting.
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Epipododphyllotoxin
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Camptothecin
* TOPOTECAN * IRINOTECAN * Natural products derived from the Camptotheca acuminata tree. * Inhibit topoisomerase I. Inhibition results in DNA damage.
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Relative myelosupression
High * Cytarabine * Alkylating agents * Doxorubicin * Daunorubicin * Vinblastine Medium * Carboplatin * MTX * 5-FU Low * Bleomycin * Vincristine * Asparaginase
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ESTROGEN INHIBITORS
Anti-estrogen approaches for therapy of hormone-positive breast cancer include: * SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs): Tamoxifen, Raloxifene * SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDs): Fulvestrant * AROMATASE INHIBITORS (AIs): Anastrozole & Letrozole, Exemestane
46
TAMOXIFEN
* SERMS bind to estrogen receptors and act as agonists or antagonist depending on the tissue. * Tamoxifen is an antagonist on breast cancer. * Tamoxifen is an agonist in nonbreast tissues. * Used for receptor-positive **breast cancer.** * Chemopreventive agent in women at risk for breast cancer.
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RALOXIFENE
* Raloxifene is an antiestrogen in the uterus and the breast, while promoting estrogenic effects in the bone to inhibit resorption. * Used for prevention of postmenopausal osteoporosis and **prophylaxis of breast cancer** in high risk postmenopausal women.
48
FULVESTRANT
* SERDs are devoid of estrogen agonist activity. * Fulvestrant binds to the estrogen receptor (ER) inhibits its dimerization and increases its degradation. * ER-mediated transcription is abolished.
49
AROMATASE INHIBITORS
* Aromatase converts androstenedione to estrone. * In postmenopausal women, this conversion is the primary source of circulating estrogens. * Aromatase inhibitors are the standard of care for adjuvant treatment of postmenopausal women with hormone receptor–positive breast cancer. ANASTROZOLE & LETROZOLE * Nonsteroidal. * Reversiblecompetitiveinhibitorsofaromatase. EXEMESTANE * Steroidal. * Irreversibleinhibitorofaromatase.
50
ANDROGEN INHIBITORS
* The preferred approach for the therapy of prostate cancer is the use of GnRH agonists, alone or in combination with an androgen receptor blocker. * GONADOTROPIN-RELEASING HORMONE AGONISTS * ANDROGEN RECEPTOR BLOCKERS
51
GONADOTROPIN-RELEASING HORMONE AGONISTS
* GOSERELIN * LEUPROLIDE * When given continuously or as a depot, GnRH agonists cause an **initial surge in LH and FSH levels, followed by inhibition of gonadotropin release.** * This results in reduction of testicular production of testosterone to castrate levels. * Testosterone levels fall to 10% of their initial values after a month. * However,they increase significantly in the beginning, causing a transient flare of tumor activity and an increase in symptoms. * The flare phenomenon can be **counteracted** by concurrent administration of **flutamide** for 2-4 weeks.
52
FLUTAMIDE
* ANDROGEN RECEPTOR BLOCKERS * Synthetic, nonsteroidal antiandrogen. * Metabolized to an active metabolite that acts as a competitive antagonist at the androgen receptor, preventing its translocation to the nucleus.
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Inhibitors of EGF Receptors
* Gefitinib: * Erlotinib: * Lapatinib: Inhibitor of EGFR and ErbB2 tyrosine kinases. * Cetuximab: mAb against EGFR * Trastuzumab: mAb against ErbB2
54
Imatinib
Inhibits the tyrosine kinase of Bcr-Abl. Inhibits c-kit (a receptor tyrosine kinase.)
55
Sorafenib
* Inhibits the serine/threonine kinase RAF, which is immediately downstream of RAS * also inhibits VEFR-2, PDGFR and other RTK so it also inhibits angiogenesis
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Bortezomib
* Inhibits the proteasome. * Induces growth inhibition and apoptosis of tumor cells with relatively few toxic effects on normal cells.
57
Sunitinib
* Inhibits VEGFR-1, VEGFR-2, and PDGFR
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ASPARAGINASE
* Most normal tissues synthesize L-asparagine in amounts sufficient for protein synthesis. * Certain neoplastic tissues, however, require exogenous source. * Asparaginase hydrolyzes serum asparagine, depriving these cells of the asparagine necessary for protein synthesis, leading to cell death.
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ASPARAGINASE - ADVERSE EFFECTS
* Hypersensitivity. * Decrease in clotting factors. * Liver abnormalities. * Pancreatitis, seizures, coma due to ammonia toxicity.
60
HYDROXYUREA
* Inhibits ribonucleotide reductase. * This leads to depletion of deoxynucleoside trisphosphate pools. * DNA synthesisis thereby inhibited. * Kills cells in S phase. * Given orally. * **Uses: **Melanoma, chronic myelocytic leukemia, carcinoma of the ovary, head and neck.
61
​Interferons alpha
Approved for hairy cell leukemia, CML, malignant melanoma and Kaposi’s sarcoma.
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