Cancer Chemotherapy

Principles
1. indicated for cancers that are not amenable to surgery or radiation therapy
2. supplemental treatment to prevent metastasis following surgery or radiation
3. Log Kill Hypothesis
  1. first order kinetics
  2. kills constant fraction of cancer cells
4. Mechanisms
  1. Interfere with cell proliferation or promote apoptosis
  2. Inhibit DNA synthesis or alter DNA structure
  3. Cell-Cycle Specific or Cell-Cycle Nonspecific
5. Combination Therapy
  1. Principles of Drug Selection
    1. individual anticancer activities
    2. different mechanisms of action
    3. different toxicities
  2. Advantages
    1. provide maximal killing with lower toxicity
    2. Effective against heterogeneous cell populations
    3. Reduces chance of resistance clones
  3. Examples
    1. ABVD
    2. CHOP
    3. MOPP
    4. CMF
    5. FEC
6. Limitations
  1. Drug Resistance
  2. Toxicities
Alkylating Agents
1. cell cycle non-specific
2. Mechanism of Action
  1. produce strong electrophiles through the formation of carbonium or ethyleneiomonium ion intermediates
    1. forms covalent linkage by alkylaation of nucleophilic moieties present in DNA
  2. Binds to **N7 of guanine, N1 + N3 A, N3 C, O6 G
3. Resistance
  1. decreased permeability
  2. increased rates of metabolism
  3. enhanced DNA repair
  4. Increased production of glutathione
    1. inactivates alkylating agents
4. Nitrogen Mustards
  1. Mechlorethamine
    1. Therapeutics
      1. Hodgkin's Lymphoma (MOPP)
      2. cutaneous T-cell Lymphoma
    2. Toxicity
      1. nausea and vomiting
      2. myelosuppression
  2. Cyclophosphamide and Ifosfamide
    1. Therapeutics
      1. C: ALL, CLL, non-Hodgkin's, breast, lung, ovarian
      2. I: sarcoma and testicular
    2. Toxicity
      1. Nausea, vomiting, myelosuppression
      2. Hemorrhagic Cystitis
        acrolein in urine
        treat with hydration and MESNA
5. Nitrosoureas
  1. Carmustine and Lomustine
    1. lipophilic
      1. cross the blood-brain barrier
    2. Toxicity
      1. Nausea, vomiting, myelosuppression
      2. Renal Toxicity
      3. Pulmonary Fibrosis
6. Triazenes
  1. Dacarbazine and Temozolomide
    1. Therapeutic Uses
      1. D: ABVD, Hodgkin's Disease, malignant Melanoma
      2. T: malignant gliomas, combo with radiation therapy
    2. Toxicity
      1. Nausea, vomiting, myelosuppression
      2. Flu-like symptoms (fever, fatigue)
7. Platinum Analogs
  1. Cisplatin, Carboplatin, Oxaliplatin
    1. No carbonium ion intermediates
      1. covalently bind to nucleophilic sites
    2. Therapeutics
      1. Cis: testicular, ovarian, cervical, bladder, head and neck, lung, combos
      2. Carb: ovarian
      3. Ox: gastric and colorectal (with 5-FU)
    3. Toxicity
      1. Cis: renal toxicity, ototoxicity, peripheral neuropathy
      2. Carb: myelosuppression
      3. Ox: peripheral sensory neuropathy (cold induced acute peripheral neuropathy), neutropenia
Antimetabolities
1. Mechanism
  1. structural analogs of endogenous metabolites
  2. replace and compete with nucleotides
2. Cell-Cycle specific Drugs
3. Folate Analogs
  1. Methotrexate
    1. folic acid anatagonist
      1. inhibits dihydrofolate reductase
        Required for thymidine and purine biosynthesis
    2. Therapeutics
      1. ALL
      2. Burkitt's Lymphoma
      3. Breast, ovary, head and neck, bladder
      4. Cannot penetrate the CNS
      5. Osteosarcoma
    3. Toxicity
      1. Myelosuppression and spontaneous hemorrhage
      2. oral ulceration and stomatitis
      3. Renal toxicity through crystallization
      4. Hepatotoxicity
      5. Defective oogenesis or spermatogenesis
    4. Mechanism of resistance
      1. reduced drug uptake
      2. Decreased affinity of DHFR
      3. Increased production of DHFR
  2. Pemetrexed
    1. Targets DHFR and thymidylate synthase
    2. Used for colon, pancreatic, mesothelioma and non-small cell lung
4. Pyrimidine Analogs
  1. 5-Fluorouracil
    1. pro-drug conversion to 5-FdUMP and 5-FdUTP
      1. inhibits thymidylate synthetase (blocks synthesis of thymidine)
      2. incorporates into RNA, interferes with function
    2. Therapeutics
      1. breast, colorectal, gastric, head and neck, cervical and pancreatic cancer
      2. Topical to treat basal cell carcinomas
      3. Capecitabine
        metastatic breast and colorectal cancer
        5'-dFdU
    3. Toxicity
      1. Gastric toxicity (why it is IV)
      2. anorexia and nausea, myelosuppression
      3. Hand-Foot Syndrome
      4. Cardiac Toxicity
  2. Cytarabine
    1. analog of 2'-deoxycytidine
      1. converted to Ara-CMP, then Ara-CTP
        Competes with dCTP
    2. Therapeutics
      1. AML
      2. ALL and CLL
    3. Toxicity
      1. myelosuppression and GI tract toxicity
    4. S-phase specific
  3. Gemcitabine
    1. analog of deoxycytidine
      1. altered to dFdCMP then dFdCDP or dFdCTP
        inhibits DNA sythesis
        dFdCDP inhibits ribonucleotide reductase
        dFdCTP causes DNA synthesis termination
    2. cell cycle nonspecific
    3. Therapeutics
      1. pancreatic cancer
      2. non-small cell lung cancer, ovarian, bladder, esophageal, head and neck
    4. Toxicities
      1. Myelosuppression
      2. Flu like symptoms
5. Purine Analogs
  1. 6-Mercaptopurine
    1. reduces purine levels, inhibiting DNA and RNA synthesis
    2. metabolized by HGPRT to TIMP
      1. blocks first step in purine synthesis
      2. blocks AMP and xanthinylic acid from inosinic acid
      3. converted to thio-guanine ribonucleotides
        inhibit DNA and RNA synthesis
    3. Therapeutics
      1. ALL
    4. Toxicities
      1. bone marrow suppression
      2. hepatotoxicity from prolonged use
      3. Allopurinol use
        blocks xanthine oxidase
        causes elevated levels of mercaptopurine
    5. Mechanism of Resistance
      1. reduced conversion of 6-MP to active nucleotide (decreased expression of HGRPT)
      2. decreased drug transport
DNA Intercalating Agents
1. AKA anti-tumor antibiotics
  1. from Streptomyces
2. DNA through intercalation
  1. block DNA and RNA synthesis
  2. causes DNA strand breaks
3. Dactinomycin
  1. Mechanism
    1. intercalates between G-C forming dactinomycin-DNA complex
      1. interferes with DNA-dependent RNA polymerase
      2. single strand breaks
  2. Therapeutics
    1. pediatric tumors: Wilm's tumor, rhabdomyosarcoma, Ewing's sarcoma
  3. Toxcitiy
    1. Severe hematopoietic suppression with pancytopenia
    2. GI symptoms
4. Anthracyclins
  1. reduce intermediates that donate electrons, forming superoxide
    1. forms destructive hydroxyl radical that cleaves DNA
  2. Toxicity
    1. irreversible dose-limiting cardiotoxicity (cardiomyopathy)
    2. Myelosuppression and GI symptoms
  3. Therapeutics
    1. Daunorubicin and Idarubicin
      1. AML
    2. Doxorubicin
      1. sarcomas, breast and lung, malignant lymphomas
    3. Epirubicin
      1. metastatic breast cancer and gastric cancer
5. Bleomycin
  1. Mechanism
    1. contains 2 copper chelating peptides
      1. forms free radicals
        causes single and double strand breaks
    2. Acts during G2
  2. Therapeutics
    1. testicular tumors (with vinblastine or etoposide)
    2. squamous cell carcinomas and lymphomas
  3. Toxicity
    1. minimally myelo- and immunosuppressive
      1. used in combination with other drugs
    2. Pulmonary Toxicity
    3. Cutaneous toxicity
    4. Hyperthermia, headache, nausea, vomiting
Microtubule Inhibitors
1. block assembly and disassembly of MTs
2. functions in metaphase
3. Vinca Alkaloids
  1. Vinblastine and Vincrstine
    1. Mechanism
      1. bind to tubulin and block ability to polymerize
    2. Therapeutics
      1. Vinblastine
        with Bleomycin and cisplatin for metastatic testicular cancers
        Part of ABVD (adriamycin [doxorubicin], bleomycin, vinblastine and dacarbazine)
        Hodgkin's Lymphoma
      2. Vincristine
        with glucocorticoids for childhood ALL
        Hodgkin's and non-Hodgkin's Lymphoma (MOPP)
    3. Toxicity
      1. Vinblastine
        myelosuppresion, GI
      2. Vincristine
        Dose-limiting neurotoxicity (peripheral neuropathy)
        low toxicity in the bone
4. Taxanes
  1. Mechanism
    1. promote polymerization and stabilize MTs
      1. prevent breakdown
  2. Therapeutics
    1. Paclitaxel and Docetaxel
      1. metastatic breast, ovarian, lung, head and neck.
    2. Docetaxel
      1. hormone-refractory prostate cancer
  3. Toxicity
    1. Neutropenia, peripheral neuropathy, hypersensitivity
Topoisomerase Inhibitors
1. Topoisomerase mediate DNA strand breakage and resealing
  1. Topo I breaks and seals single stranded
  2. Topo II breaks and seals double stranded DNA
2. Epipodophyllotoxins
  1. Etoposide and Teniposide
    1. Mechanism
      1. inhibit Topo II, causing DNA damage
    2. semisynthetics of podophyllotoxin
    3. Therapeutics
      1. Etoposide
        testicular carcinoma, lung cancer, non-Hodgkin's Lymphoma
      2. Teniposide
        ALL
    4. Toxicity
      1. dose-limiting myelosuppression (neutropenia)
      2. Oral Mucositis
3. Camptothecin Analogs
  1. Mechanism
    1. inhibit Topo I
  2. Therapeutics
    1. Irinotecan
      1. advanced colon cancer
      2. lung, ovarian, cervical, brain tumors
    2. Topotecan
      1. ovarian and small cell lung cancer
  3. Toxicity
    1. severe neutropenia and severe diarrhea
Hormones and Antagoists
1. used for hormone dependent neoplasms
  1. breast and prostate cancer
2. glucocorticoids
  1. treat lymphocytic leukemias and lymphomas
  2. Mechanism
    1. inhibit mitosis in lymphocytes
  3. no immunosuppression and well tolerated
  4. Therapeutics
    1. Prednisone
      1. ALL
      2. part of MOPP and CHOP for Hodgkin's and non-Hodgkin's, multiple myeloma and CLL
    2. Dexamethasone
      1. Dexamethasone
        in conjuction with radiation therapy
        reduces edema to brain and spinal cord tumors
3. Estrogen antagonists
  1. breast cancer
4. Androgen antagonists
  1. prostate cancer
5. Selective Estrogen-Receptor Modulators
  1. Tamoxifen
    1. competes with estradiol for ER binding
    2. Therapeutics
      1. ER-positive metastatic breast cancer or adjuvant therapy following primary breast tumor excision
      2. prevention of breast cancer in high-risk patients
    3. Toxicity
      1. hot flushes, hair loss, nausea, vomiting
      2. increase risk of endometrial cancer and thromboembolic events
6. Selective Estrogen-Receptor Downregulators
  1. Fulvestrant
    1. Mechanism
      1. binds to ER, preventing dimerization
      2. Reduces number of ER molecules
    2. Therapeutics
      1. postmenopausal women with ER-positive metastatic breast cancer
7. Aromatase Inhibitors
  1. inhibit aromatase enzyme, causing estrogen decrease
  2. Aminoglutethamide
    1. weak inhibitor
    2. significant toxicity
  3. Anastrozole
    1. potent and selective inhibitor
    2. ER-positive breast cancer in postmenopausal women
8. Prostate Cancer Treatments
  1. Leuprolide (Lupron) and Goserelin (Zoladex)
    1. GnRH analogs
      1. inhibit release of LH and FSH
        Decreased Testosterone Production
  2. Complete androgen ablation therapy involves combination of GnRH analogs and AR blockers
  3. Flutamide and Bicalutamide
    1. nonsteroidal androgen-receptor blockers
      1. compete for androgen receptor and prevent its translocation to nucleus
Miscellaneous Agents
1. Hydroxyurea
  1. inhibits ribonucleside diphosphate reductase
    1. converts ribonucleosides to deoxyribonucleosides
  2. Therapeutics
    1. myeloproliferative neoplasms, polycythemia vera and essential thrombocythemia
2. Retinoids
  1. treats acute promyelocytic leukemia
  2. induces differentiation in leukemic promyelocytes
3. Arsenic Trioxide
  1. treats relapsed APL
4. Thalidomide
  1. treats multiple myeloma and myelodysplastic syndromes
5. Interferons
  1. IF alpha for hairy cell leukemia, CML, AIDS relate Kaposi's sarcoma
6. Tyrosine Kinase Inhibitors
  1. Imatinib
    1. inhibits Abl kinase, PDGFR and c-kit
    2. treats CML and GI tumor
  2. Gefitinib and Erlotinib
    1. inhibit EGFR tyrosine kinase
    2. treats non-small cell lung cancer
7. Monoclonal Antibodies
  1. Rituximab
    1. targets CD20 B-cell antigen
    2. Treats non-Hodgkin's Lymphoma
  2. Trastuzumab
    1. antibody against HER2/neu
    2. treats HER2/neu-overexpressing breast cancer
  3. Cetuximab
    1. antibody against EGFR1 (ErbB1
    2. approved for EGFR-positive colorectal cancer

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Cancer Chemotherapy

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	Erstellt von Jeff Amos vor mehr als 10 Jahre