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173 Cards in this Set
- Front
- Back
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What cell cycle phase(s) do most anti-cancer agents target?
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S-phase, because this is where all proliferation occurs
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What class of drug is Mechlorethamine?
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Alkylating Agents
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MOA of Alkylating Agents
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Crosslinking of DNA, and Alkylation (or carbamoylation) of DNA and/or protein
The end result is DNA damage |
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Common Property of Alkylating agents
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* They become strong electrophiles through formation of carbonium ion intermediates, or transition complex with target molecules
* This reaction leads to formation of covalent bond by alkylation of nucleophilic moieties (phosphate, amino, sulfhydryl, hydroxyl, carboxyl, imidazole groups) |
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Phosphoramide Mustard
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Active metabolite of Cyclophosphamide (also toxic)
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Mechanism of Resistance of Alkylating Agents
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* Acquired resistance is a common event; resistance to one agent often imparts cross resistance to others.
* Decreased permeation of actively transported drugs. * Increased activity of DNA repair enzymes. * Increased production of nucleophilic substances, principally thiols such as glutathione, that can conjugate with and detoxify electrophilic intermediates. * Alternative: Methods are used to deplete glutathione, e.g. a sulfhydryl compound, BSO, buthionine sulfoximine. * Increased rates of metabolism of activated forms of cyclophosphamide to its inactive metabolites. |
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Toxicities of Alkylating Agents
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* As a class, highly leukemogenic.
* Cumulative bone marrow suppression. * Toxic (a lesser extent) to intestinal mucosa. * Pulmonary fibrosis. * At high-dose regimen, endothelial damage. |
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Examples of Alkylating Agents
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* Nitrogen Mustards –Mechlorethamine, Cyclophosphamide, Chlorambucil
* Nitrosourea - Carmustine * Alkyl sulfonate - Busulfan * Triazenes – Dacarbazine * Platinum Compounds – Cisplatin, Carboplatin, Oxaliplatin |
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What are the sub-classes of Alkylating agents, how are they classified, examples of each?
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Two classes of agents in terms of their effect on DNA:
1. Intrinsically Reactive – active by itself or direct acting * Mechlorethamine * Carmustine * Busulfan * Chlorambucil * Cisplatin * Carboplatin * Oxaliplatin 2. Require Metabolic Activation to alkylating species * Cyclophosphamide |
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Mechanisms of resistance for
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1. Impaired transport into cells
2. Impaired polyglutamate formation 3. (MAJOR) Increased of altered DHFR 4. decreased thymidylate synthase (b/c much lower levels of DHFR in the absence of this enzyme) |
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Examples of Antimetabolites
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* Folic Acid and Analogs
- Methotrexate - Pemetrexed * Pyrimidine Analogs - Fluorouracil (5-Fluorouracil, 5-FU), - 5-FU analog Capecitabine Cytarabine (Cytosine Arabinoside, AraC) - Gemcitabine * Purine Analogs - Mercaptopurine * Others - Fludarabine Phosphate – Fludarabine - Hydroxyurea |
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Antimetabolites interfere with DNA synthesis – means which phase of cell cycle arrest?
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S
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Which drug is the most important 5-FU analog; a drug with proven activity against colon and breast cancers.
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Capecitabine
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Which 5-FU analog is a drug with proven activity against colon and breast cancers?
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Capecitabine
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What kind of tumor is most susseptible to Capecitabine?
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Tumors with elevated thymidine phosphorylase activity seem particularly susceptible to this drug.
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How is Capecitabine activated?
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Converted to 5’-deoxy-5-fluoro-cytidine by carboxylesterase in liver (and other normal & malignant tissues) followed by to 5’-deoxy-fluorodeoxyuridine by cytidine deaminase. Final activation occurs when thymidine phosphorylase cleaves off 5’-deoxy sugar, leaving intracellular 5-FU.
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Mechanism of Resistance of 5-FU Analog Capecitabine
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Loss or decrease in activity of enzymes necessary for activation of 5-FU to F-dUMP.
Amplification of thymidylate synthase, and altered thymidylate synthase that is not inhibited by F-dUMP. |
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Toxicities of 5-FU Analog Capecitabine
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Toxicities include: severe diarrhea, and toxic effects similar to other chemotherapeutic agents against cancer.
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What is Cytarabine(Cytosine Arabinoside; AraC) used for?
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Most important antimetabolite used in therapy of acute myelocytic leukemia.
Single most effective agent for induction of remission in this disease. |
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What is the MOA of Cytarabine(Cytosine Arabinoside; AraC)?
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Inhibition of DNA through Inhibition DNA polymerase and DNA elongation.
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What is Gemcitabine(2,2-difluorodeoxy cytidine, dFdC) used for?
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Most important antimetabolite in clinic in recent years, and part of first-line regimen for patients with metastatic pancreatic and non-small cell lung cancers.
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Gemcitabine Mechanism of Action
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Mechanism of action is similar to AraC, however, efficacy is not confined to S-phase; it is equally effective against confluent and growing cells.
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Primary toxicity of Gemcitabine
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myelosuppressive, others include flu-like syndrome.
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Alkylating Agents
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* Nitrogen Mustards
- Mechlorethamine - Cyclophosphamide - Chlorambucil * Nitrosourea - Carmustine * Alkyl sulfonate - Busulfan * Triazenes – Dacarbazine * Platinum Compounds – Cisplatin - Carboplatin - Oxaliplatin |
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Antimetabolites
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* Folic Acid and Analogs
- Methotrexate - Pemetrexed * Pyrimidine Analogs - Fluorouracil (5-Fluorouracil, 5-FU), - 5-FU analog Capecitabine - Cytarabine (Cytosine Arabinoside, AraC) - Gemcitabine * Purine Analogs - Mercaptopurine * Others - Fludarabine Phosphate - Fludarabine Hydroxyurea |
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Microtubule (Mitotic Spindle) Agents
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* Vinca Alkaloids
– Vinblastin - Vincristine - Vinorelbine *Others: - Paclitaxel (Taxol) - Docetaxel (Taxotere) – Promote polymerization of microtubules. |
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Topoisomerase Targeting Agents
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* Etoposide
* Teniposide * Camptothecin and analogs (Topotecan and Irinotecan) |
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Antibiotics
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* Dactinomycin (Actinomycin D)
* Doxorubicin and Analogs * Mitoxantrone * Bleomycin |
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The Altered Phenotypic Traits of Tumor Tissue
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1. Resistance to anti-growth signal (TGFbeta downregulation, Rb mutation, C-m yc overexpression)
2. Resistance to apoptosis (NF-kapaB activation, p53 mutation) 3. Invasion and metastasis (loss of cell-cell adhesion eg. E-cadherin inactivation, increased MMP secretion) 4. Inflammation (Cox-2 overexpression, cytokine production) 5. Increased angiogenesis (secretion of VEGF, FGF) 6. Lack of senscence (upregulation of telomerase) 7. Constitutive mitotic signaling (E GFR, Ras activation) |
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What are six leading cancer types in the United States?
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1. Lung
2. Prostate 3. Breast 4. Colon 5. Lymphoma 6. Urinary bladder |
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What are the principles and benefits of combination chemotherapy?
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Principles:
- Choose non-overlapping mechanism of action of the drug. - Choose drugs with the least overlapping major toxicities. Benefit(s): - Combination gives better activity than single agent, because there would be side effects of combined treatments. |
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True or False?
In addition to growing cancer cells, normal cells are damaged by anti-cancer drugs. |
True
Similar to growing cancer cells, normal tissue that proliferate (bone marrow, hair follicle, intestinal epithelium) are damaged by anti-cancer drugs, limiting their use. |
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What are the main sub-classes of Alkylating agents?
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1. Intrinsically Reactive – active by itself or direct acting
- Mechlorethamine - Carmustine - Busulfan - Chlorambucil - Cisplatin, Carboplatin, Oxaliplatin 2. Require Metabolic Activation to alkylating species - Cyclophosphamide |
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Mechanism of Action of Carmustine
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The degreadation of carmustine (BCNU) causes generation of alkylating and carbamoyling intermediates which pind to DNA and other proteins
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Mechanism of Action of Cyclophosphamide
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picture slide
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Mechanism of Resistance of Alkylating Agents
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* Acquired resistance is a common event; resistance to one agent often imparts cross resistance to others. * Decreased permeation of actively transported drugs. * Increased activity of DNA repair enzymes. * Increased production of nucleophilic substances, principally thiols such as glutathione, that can conjugate with and detoxify electrophilic intermediates. Alternative: Methods are used to deplete glutathione, e.g. a sulfhydryl compound, BSO, buthionine sulfoximine. * Increased rates of metabolism of activated forms of cyclophosphamide to its inactive metabolites.
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Toxicities of Alkylating Agents
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* As a class, highly leukemogenic. * Cumulative bone marrow suppression. * Toxic (a lesser extent) to intestinal mucosa. * Pulmonary fibrosis. * At high-dose regimen, endothelial damage.
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How are platinum compounds different from other Alkylating Agents?
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* Exact mechanism(s) of action not known, but they form DNA adducts. * Major resistance is via DNA repair
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What is Cisplatin used for?
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broad activity, specifically useful in epithelial malignancies.
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What major toxicities are associated with Cisplatin?
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Major toxicities include renal proximal tubular necrosis, ototoxicity.
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What is Carboplatin used for?
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Ovarian cancer
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What major toxicities are associated with Carboplatin?
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Major toxicities include renal proximal tubular necrosis, ototoxicity. Similar to Cisplatin but less prevalent.
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What is Oxaliplatin used for?
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A wide range of cancers including ovarian and cervical cancers. Generally more effective than Cisplatin or Carboplatin because DNA repair enzyme proficient cells are equally effective.
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"
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Methotrexate
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What event lead to the development of anti-folate analogs that specifically target folate-dependent enzyme targets of methotrexate?
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A finding that methotrexate, an inhibitor of dihydrofolate reductase (DHFR), also inhibits folate dependent enzyme of purine and thymidine synthesis
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Which agent is a Multitargeted Antifolate (MTA)?
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"Pemetrexed, an important new folate analong which inhibits thymidylate and purine biosynthesis, in addition to dihydrofolate reductase (DHFR) inhibition.
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What cancers has Pemetrexed shown activity against?
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colon cancer, mesothelioma, and non-small cell lung cancer.
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What are the two important enzymes targeted by folate analogs?
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Thymidylate synthase and dihydrofolate reductase
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Which folate analogs block the regeneration of tetrahydrofolate?
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aminopterin and methotrexate
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What is the MOA of folate analogues?
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"* To function as a cofactor in one-carbon transfer, folate (dihydrofolate) is reduced by DHFR to tetrahydrofolate (FH4). * Single-carbon fragments are added enzymatically to FH4 (for example, conversion from serine to glycine), leading to 5,10-methylene FH4. * dUMP is converted to dTMP where thymidylate synthase transfers one carbon group to dUMP from methylene FH4 converting it to FH2. * DHFR is primary site of action for most folate analogs. Its inhibition leads to toxic effects via depletion of FH4 required for synthesis of purines and thymidylate (dTMP), precursors of DNA/RNA synthesis. This causes interruption of DNA/RNA synthesis. * At the same time, it causes vast accumulation of toxic substrate FH2 polyglutamate.
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What are the major mechanisms of resistance to Methotrexate?
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1. Impaired transport of drug into cells 2. Impaired polyglutamate formation 3. (MAJOR) increased or altered dihydrofolate reductace 4. decreased thymidylate synthase
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What are the unique toxicities of methotrexate?
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* Toxic against rapidly growing normal cells of bone marrow and GI epithelium. * Hepatotoxicity: fibrosis and cirrhosis * Nephrotoxicity due to drug precipitation
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What is the MOA of Pyrimidine Analogs 5-FU?
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* Inhibit biosynthesis of pyrimidine nucleotides. * Mimic these natural metabolites to such an extent that they interfere with the synthesis or function of nucleic acids. * The best characterized agents in this class are halogenated pyrimidines: fluorouracil and 5-fluorouracil (5-FU) * By several activation pathways, fluorouracil is converted in vivo to fluorodeoxyuridylate (F-dUMP) that irreversibly inhibits thymidylate synthase after acting as a normal substrate. * This inhibits the methylation of dUMP.
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How does F-dUMP inhibit methylation of dUMP?
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"* A –SH group of enzyme adds to C-6 of F-dUMP. Methylene FH4 then adds to C-5 of this intermediate. * In case of dUMP, a hydride ion of folate is subsequently shifted to methylene gr, and a proton is taken away from C-5 of bound nucleotide. * However, F+ cannot be abstracted from F-dUMP by enzyme, and so catalysis is blocked at the stage of covalent complex formed by F-dUMP, methylene FH4 and –SH of enzyme.
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Does Cytarabine (Cytosine Arabinoside; AraC) need to be activated?
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Yes, must be activated to 5’-mono-phosphate nucleotide (AraCMP)
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How is Cytarabine (Cytosine Arabinoside; AraC) activated?
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deoxycytidine kinase activates to 5’-mono-phosphate nucleotide (AraCMP)
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Mechanism of Resistance of Cytarabine
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"* Increased cytidine deaminase, a degradation enzyme that deaminates AraC to non-toxic metabolite, arauridine. * Decreased levels of deoxycytidine kinase that converts AraC to AraCMP. * A second degradation enzyme dCMP deaminase, converts AraCMP to inactive metabolite AraUMP.
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Primary toxicities of Cytarabine
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myelo-suppression and others include GI disturbances.
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What are Mercaptopurine and 6-Mercaptopurine (6-MP) used for?
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"* Useful in the treatment of malignant diseases. * Also used as immunosuppressive and anti-viral agent.
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What is the MOA of Mercaptopurine and 6-Mercaptopurine (6-MP)?
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* Inhibits multiple pathways in conversion of inosine monophosphate (IMP) to adenine and guanine nucleotides. * Must be activated to nucleotide form by hypoxanthine guanine phosphoribosyl transferase (HGPRT).
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Mechanism of Resistance for Mercaptopurine and 6-Mercaptopurine (6-MP)?
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"* Acquired resistance – deficiency or complete lack of HGPRT. * Decreased affinity of enzyme for substrate. * Others include: decreased drug transport, increased rate of degradation of drug, increased activity of MDR protein.
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What are toxicities of Mercaptopurine and 6-Mercaptopurine (6-MP)?
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hyperuremia, bone marrow suppression, nausea, vomiting, jaundice.
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What is Fludarabine Phosphate Fludarabine used for?
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"Active in chronic lymphocytic leukemis and low-grade lymphomas.
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What is the MOA of Fludarabine Phosphate Fludarabine?
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* After rapid dephosphorylation to nucleoside fludarabine by membrane 5’-ectonucleotidase, it is rephosphorylated intracellularly by deoxycytidine kinase to active triphosphate. * Inhibits DNA polymerase etc, and is incorporated into DNA and RNA. * Although the exact mechanism of activity is not well understood, it causes DNA chain termination and induction of apoptosis.
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What are toxicities of Fludarabine Phosphate Fludarabine?
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myelosuppression, nausea and vomiting, and chills and fever.
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What is the MOA of Hydroxyurea?
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* Inhibits ribonucleoside diphosphate reductase, an enzyme that catalyzes reductive conversion of ribonucleotides to deoxyribonucleotides; a crucial and a rate limiting step in the biosynthesis of DNA. * Specific for S-phase.
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What is the major mechanism of resistance for Hydroxyurea?
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elevation of reductase activity
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What are toxicities of Hydroxyurea?
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hematopoietic depression, GI disturbances and mild dermatological reactions.
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What is oncogene addiction and how does oncogene addiction relate to intracellular signaling?
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Tumor cells become ‘addicted’ to that growth stimulatory pathway constitutively activated as a result of protooncogene or tumor suppressor gene mutation. Thus, if a cancer cell has dozens of mutations associated with cell division but they are primarily using the mutated Kras pathway to provide signals that allow them to grow, then inhibiting the Kras pathway with various drugs will interfere with cancer growth. This is true even though several other pathways could theoretically be used by the cell. In contrast, normal cells are not addicted to any particular pathway.
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Why is it important to diagnose cancer early?
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If tumors could be detected very early, before their inherent genetic instability allows them to make genetically variant daughter cells that are resistant to drugs or better at metastasizing, this would greatly enhance cancer prevention and therapy
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What are the differences between benign and malignant tumors?
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Growth rate
- Benign * low mitotic rate * normal mitoses * normal nucleoli - Malignant * high mitotic rate * abnormal mitoses * large nucleoli Differentiation - Benign * resembles normal * maintains normal functions - Malignant * often poor * lost or altered function Spread - Benign * encapsulated * no invasion * no metastases - Malignant * no capsule * locally invasive * matastases common |
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How are tumors named?
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By tissue type and Behavior:
- Benign = -oma - Malignant = ...carcinoma or ...sarcoma |
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Papilloma
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Benign tumor in the stratified squamous epithelium
or Benign tumor in the transitional epithelium |
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Squamour cell carcinoma
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Malignant tumor in the stratified squamous epithelium
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Adenoma
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Benign tumor in a glandular epithelium
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adenocarcinoma
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Malignant tumor in a glandular epithelium
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transitional cell carcinoma
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Malignant tumor in the transitional epithelium
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Fibroma
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Benign non-endothelium fibrous tissue tumor
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fibrosarcoma
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Malignant non-endothelium fibrous tissue tumor
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lipoma
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Benign non-endothelium fatty tumor
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liposarcoma
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Malignant non-endothelium fatty tumor
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leiomyoma
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Benign non-endothelium smooth muscle tumor
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leiomyosarcoma
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Malignant non-epithelial smooth muscle tumor
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rhabdomyoma
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Benign non-epithelial striated muscle tumor
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rhabdomyosarcoma
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Malignant non-epithelial striated muscle tumor
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synovioma
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Benign non-epithelial synovium tumor
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synovial sarcoma
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Malignant non-epithelial synovium tumor
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chondroma
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Benign non-epithelial cartilage tumor
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chondrosarcoma
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Malignant non-epithelial cartilage tumor
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osteoma
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Benign non-epithelial bone tumor
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osteosarcoma
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Malignant non-epithelial bone tumor
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haemangioma
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Benign non-epithelial blood vessel tumor
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angiosarcoma
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Malignant non-epithelial blood vessel tumor
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benign taratoma
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Benign non-epithelial germ cell tumor
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malignant teratoma
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Malignant non-epithelial germ cell tumor
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naevus
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Benign non-epithelial neuroectoderm tumor
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melanoma
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Malignant non-epithelial neuroectoderm tumor
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What is the evidence that tumors change and evolve with time?
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the growth of cancer compares to fetal growth, how neoplastic growth results from disturbance of the normal balance between proliferation and apoptosis, genes involved in the cell cycle.
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What causes cancer? How do they know?
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Environmental factors coupled with genetic succeptibility cause cancer. Remember "Cappadocia, mesothelioma
villages" |
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What is the evidence that smoking causes cancer?
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PAH and NNK are metabolically activated which leads to DNA adducts. This in tern leads to mutations in k-RAS, p-53 and other critical genes.
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How does the tumor microenvironment/stroma affect tumor cells?
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Tumor cells exist in an intimate cross-signaling environment with stromal (mesenchymal) cells, these include macrophages which can affect tumor growth in many ways.
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What is the difference between innate and adaptive immune cells?
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Innate immune cells: neutrophils, macrophages, dendritic cells and natural killer cells
Adaptive immune cells: T-cells and B-cells |
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What is the significance of tumor angiogenesis?
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Like all tissues, a tumor cannot survive or grow without a blood supply. Tumor cells release factors that stimulate new blood vessel growth. In normal tissues, epithelial cells secrete inhibitors of endothelial cell growth, and vice-versa. As the tumor progresses (becomes more advanced), the nature of these signals changes and each cell type stimulates the growth of the other.
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How does tumor angiogenesis relate to new drug discovery?
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Anti-angiogenic drugs are being applied along with conventional cytotoxic agents. The great advantage to their use is that endothelial cells are genetically stable, like all normal cells, and won’t mutate to become resistant to these drugs.
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What is EMT (epithelial-mesenchymal transition)? How does this relate to metastasis? What are the stages of metastasis?
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. Once there, tumor cells undergo MET (mesenchymal-epithelial transition) to become more epithelial-like as they grow into a new tumor at another body site. This tumor will usually be recognizable as having been derived from the original primary tumor, but will be more advanced (and cellularly heterogeneous and thus harder to kill) than the primary tumors. Platelets aggregate around tumor cells in the circulation and protect them as a physical barrier from being killed. The platelets also secrete factors that enhance tumor cell survival. Each type of cancer has characteristic organ sites they metastasize to, but within these trends show great individual variation.
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What is the mechanism of cachexia?
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Tumors release TNFa, which in large concentrations can cause cachexia (a general weakening and appetite loss) and a sepsis-like condition.
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Why are cancer patients more sensitive to infection?
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* Neutropenia
* Abnormal microbial flora * Defective cell-mediated immunity * Defective humoral immunity * Malnutrition * Splenectomy * Impaired monocyte-macrophage system * Impaired chemotaxis, phagocytosis, bactericidal activity * Broken physical defence barriers |
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How do tumors escape immune surveillance?
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White blood cells infiltrate into tumors, including macrophages. These are recruited from the circulation and secrete many factors that stimulate tumor growth, depress tumor apoptosis, and cripple the adaptive immune system so the body’s natural defenses are inadequate to fight the disease. Therapies are aimed at re-activating macrophages such that they again become anti-tumor (can kill tumor cells) as they were in cancer-free people and at very early stages of tumor growth are being used along with conventional cytotoxic treatments.
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How prevalent is cancer in teh US?
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2nd most common cause of death in US
1,479,350 new diagnoses in 2009 562,340 deaths |
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Define chemoprevention
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Chemoprevention –the use of specific natural or synthetic agents to reverse, suppress or prevent the carcinogenic process, thereby preventing the development of clinically evident cancer
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Define Primary chemoprevention patient
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Primary –general population of healthy individuals at risk
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Define Secondary chemoprevention patient
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Secondary –individuals with premalignant lesions to prevent progression to cancer
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Define Tertiary chemoprevention patient
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Tertiary –prevention of a second primary cancer
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Define early detection
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Early detection –of a premalignant or early stage cancer
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Breast Cancer Chemoprevention
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192,370 new diagnoses
40,170 deaths 70-85% of sporadic breast cancers are ER+ Chemoprevention is aimed at altering ER stimulation |
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How is it determined who should receive Breast Cancer Chemoprevention?
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Gail Model
Age Age at menarche Age at first live birth or nulliparity Number of breast biopsies History of atypical hyperplasia Number of first-degree relatives with breast cancer Race/Ethnicity |
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Who is included in the Primary Chemoprevention Population for breast cancer?
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Genetic mutations
First degree relatives with breast or ovarian History of thoracic irradiation Gail model 5-year risk ≥1.7% |
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Who is included in the Secondary Chemoprevention Population for breast cancer?
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Lobular carcinoma in situ (LCIS)
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Chemoprevention for Women at high risk for breast cancer
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Mastecomyor bilateral oophrectomy
Only recommended for those with LCIS, compelling family history or known BRCA mutation Can decrease risk 90-95% Pharmacological prevention: SERMs Recommended for most high risk women ≥35yo Contraindicated in women with h/x of thrombosis, TIA or potential pregnancy Tamoxifen Raloxifene |
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Tamoxifen (breast cancer)
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FDA approved for risk reduction of breast cancer in those at high risk or with ductalcarcinoma in situ (DCIS)
20mg daily for 5 years Pre-and post-menopausal |
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Raloxifene (breast cancer)
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FDA approved for risk reduction of invasive breast cancer in post-menopausal women at high risk or with osteoporosis
60mg daily for 5 years Post-menopausal ONLY |
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What are the Pros for using SERMs as chemoprevention in breast cancer?
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Increase bone mineral density
Reduce LDL and total cholesterol |
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What are the Cons for using SERMs as chemoprevention in breast cancer?
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Tamoxifen increases endometrial proliferation
2x risk of endometrial cancer Thrombosis May increase pro-coagulant production in liver Not for women with h/o DVT or PE, on anticoagulant therapy, smokers Should be held 2-4 weeks prior to surgeries Cataracts Tamoxifen > Raloxifene Not if pregnant, planning to become pregnant or breastfeeding |
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Which SERM requires metabolism of active metabolites through CYP3A4, 2C9 and 2D6?
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Tamoxifen
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Which SERM has an active parent compound and is affected by hepatotoxicity?
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Raoxifene
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PROS and CONS of Tamoxifen
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Pros
Effective Lots of data on long-term use Osteoporosis prevention (post-menopausal only) Can be used in pre-menopausal women Cons Menopausal sxs DDI 2D6 inhibitors (SSRIs) Warfarin 3A4 and 2C9 inhibitors/inducers Cost: $100/month x12 months x5 years= $6000 |
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PROS and CONS of Raloxifene
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Pros
Effective Osteoporosis prevention (FDA) Less risk of thrombosis, endometrial cancer, cataracts Cons Weight gain Menopausal symptoms Sexual dysfunction slightly worse (STAR) DDI Cholestyramine Cost: $123/month x12 months x5 years= $7380 |
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Prostate Cancer Chemoprevention
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3rd most common cancer worldwide
146,970 new diagnoses in US in 2009 49,920 deaths in US in 2009 Chemoprevention aimed at decreasing androgen stimulation of prostate tissue |
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Who should receive Prostate Cancer Chemoprevention?
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Primary
Patient-specific Risk assessment Elevated PSA levels Rapid PSA velocity Sub-Saharan African ethnicity Family history Secondary High-grade prostate epithelial neoplasia(HGPIN) |
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Prostate Cancer Chemoprevention for high-risk men
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Digital Rectal Exam and PSA starting at 40yo
Subsequent screening depending on results Some controversy over when to pursue further testing 5αreductase inhibitors Finasteride Dutasteride |
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MOA of 5α reductase inhibitors
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Inhibit 5α reductase inhibitors so testosterone cannot be converted to DHT
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Pharmacological chemoprevention for prostate cancer
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Finasteride
5mg once daily x7 years Dutasteride 0.5mg once daily x4 years Not FDA-approved Significant increase in high-grade, aggressive tumors compared to placebo (37% v 22%) Patients did not have more extensive disease Reanalysis showed no increased risk NEJM 2003; 349(3): |
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REDUCE trial
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8231 men 50-75yo
Primary endpoint: prevalence of cancer on prostate biopsies at 2 & 4 years Preliminary results Dutasteride reduced risk by 23% at 4 years No increase in high-grade, aggressive disease |
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ADRs associated with 5α reductase inhibitors
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ADE
Sexual dysfunction Impotence, decreased libido, ejaculation disturbances Gynecomastia Does not decrease with continued use Caution with liver disease Pregnant women or those trying to conceive should NOT handle Wear gloves |
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PROS and CONS of Finasteride use for chemoprevention of prostate cancer
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Pros
Effective Cons May increase risk of high-grade tumors ADE Muscle weakness Dizziness, postural hypotension |
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PROS and CONS of Dutasteride use for chemoprevention of prostate cancer
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Pros
Lower incidence of sexual dysfunction Inhibits both isoformsof 5AR Cons May increase TSH Awaiting full results |
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Prostate Cancer: Chemoprevention, or not?
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* Pros
Reduction in risk Improves sxs of BPH Better early detection Decreases HGPIN *Cons No proven effect on mortality Unsure if increases risk of high-grade tumors Sexual side effects Cost |
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Colorectal Chemoprevention
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3rd most common cancer worldwide
146,970 new diagnoses in US in 2009 49,920 deaths in US in 2009 Normal colon leads to polyp leads to cancer Chemoprevention aimed at reducing polyp formation and development |
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Colorectal Cancer Cehmoprevention: ASA/NSAIDs/COX-2 inhibitors
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Epidemiological data
Aspirin, NSAIDs and COX-2 inhibitors may prevent polyp formation Studied in patients with familial syndromes 4-6 aspirin per week can decrease incidence by 30-50% |
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Why not give everyone aspirin?
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* Pros
Effective ASA cardioprotective Consider in patients with familial syndromes or personal h/o *Cons Benefit may take 10-20 years Benefit not maintained after d/c Higher doses GI bleed risk Increased cardiovascular risk |
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Cervical Cancer Chemoprevention
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11,270 women in the United States/yr
4,070 will die this year Routine Pap smears decrease morbidity/mortality in developed countries 90% detection Cervical cancer is the second most common cancer among women worldwide 83% of cases occurring in developing countries |
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Discuss Cervical Cancer Risk Factor: Human Papillomavirus(HPV) Infection
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Worldwide prevalence ~ 10%
Small DNA viruses Role in cervical cancer Large link to viral oncogenes E6 and E7 Effects cell cycle/growth arrest signals Types 16 and 18 implicated |
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Chemoprevention fo Cedrvical cancer
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Vaccination with Gardasil
• QuadrivalentHPV vaccine (types 6, 11, 16, 18) • Indicated in females – Age 9-26 • Administration – 3 injections over 6 months – ~$400/series |
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Gardasil
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Efficacy
~95% of women protected against types 16/18 >98% retain seroconversion at 5.5 years Relatively safe Injection site reactions Some anaphylactic reactions have occurred Two cases of Guillain-Barre syndrome reported |
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Gardasil Pearls
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Does not treat cervical cancer or genital warts
Not to use in pregnant women Do not use if severely allergic to yeast Must continue routine screening Duration of action? unknown |
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Diet/Supplements for Chemoprevention
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Vitamin A for lung
Vitamin E/selenium for prostate Vitamin D/calcium for colorectal Diet/alcohol consumption |
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Vitamin A (Retinoids)
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Multiple dietary sources
Antioxidant Epidemiological studies suggest may protect against development of lung cancer in smokers |
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Trials involving Vitamin A (Retinoids) and the bottom line
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ATBC trial
Men who took beta-carotene had 18% increased risk of lung cancer, 8% increased mortality risk Follow-up period of 8 years: Men in beta-carotene group with 7% increased mortality CARET 28 percent more lung cancers were diagnosed and 17 percent more deaths occurred after 4 years of supplementation Associated with increased risk of lung cancer in smokers |
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Selenium and Vitamin E
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Found in plants grown in Se-rich soil, meat Activation of DNA repair, p53 tumor suppressor gene Antioxidant Found in plants grown in Se-rich soil, meat Activation of DNA repair, p53 tumor suppressor gene |
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What was the outcome of the SELECT trial?
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No difference between placebo, vit E, slelenium, and vit E and selenium combo therapy
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Calcium and Vitamin D
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Calcium
Binds fatty acids and bile in gut lumen, inhibits gut mucosal proliferation Prostate Ca >2gm/day associated with increased risk Vitamin D Induction of apoptosis, inhibition of cell proliferation, modulates calcium absorption Increased intake may be associated with a decrease in colorectal cancer, other GI tumors |
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NIH-AARP Diet and Health Study
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>492K US men and women aged 50-71yo
Dietary Ca ≥1300mg/day associated with decreased overall cancer risk in women Higher dairy food intake associated with decreased risk of digestive tract cancers Higher calciumintake associated with decreased risk of colorectal cancer |
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Fiber
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Increased fecal volume, dilution of carcinogens due to increased bulk, faster transit time and stimulation of gut flora decreases exposure to carcinogens
Colorectal cancer Overall inconsistent benefit EPIC suggested up to 40% decrease compared to low-fiber diets Breast cancer Difficult to dissociate from impact of fat in diet |
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Dietary Fat
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Association between animal fat and increased risk of breast, colorectal cancer
Closely linked to obesity, other poor dietary choices |
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Alcohol Consumption
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Million Women Study (the UK)
1.28 million middle-aged women Studied moderate alcohol consumption |
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Alcohol and Cancer Risk
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Additional Cancer Risk/1000 Women with1 Additional Drink/Day
Overall 15 Breast 11 Oropharyngeal 1 Rectal 1 Esophageal/Laryngeal 0.7 Hepatocellular 0.7 |
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Cause Cancer?
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Grilled foods
Carcinogens are generated during charring Artificial sweeteners Laboratory data suggest aspartame and saccharin can be carcinogenic in rats Fluoride Increase in osteosarcomain rats |
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In a Nutshell…what are the nutritional and supplement recommendations?
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Eat a well-balanced diet
Obtain most food from plant sources Maintain a healthy weight Choose whole grains Limit processed foods And now… Protect your bones! Limit alcohol intake |
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Cancer Prevention Screening Goals
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Increase detection of precancerous lesions
Detect cancers prior to spread |
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Skin Cancer Screening
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Most common cancer diagnoses in US
8,650 deaths in US in 2009 US lifetime risk: 1 in 55 adults |
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Types of Skin Cancer
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Squamous Cell
Basal Cell Melanoma |
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Risk Factors for Melanoma
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Many nevi, irregular nevi, large nevi
Family history Places with intense, year-round sunshine UV radiation increases up to 5% for every 1000 feet above sea level Fair skin Inability to tan Sun exposure Severe sunburns as a child |
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Screening for Melanoma
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Asymmetry
Border irregularity Color variegation Diameter >6mm Evolution |
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Skin Self-Exam Technique
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Performed monthly
Head to toe Scalp Include non sun-exposed areas Underarms Between fingers & toes, nail beds Report any suspicious nevi to physician |
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Skin cancer prevention
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Visual self-examination
>90% of melanomas recognized by naked eye Cover up Long sleeves, wide-brimmed hat UV-blocking sunglasses to protect eyes Use a sunscreen SPF 15 or higher UVB protection Reapply q2 hours Limit intense sun exposure Tanning beds |
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Why Colorectal Cancer Screening
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Stage at Diagnosis
5-year Survival I >90% II 70-85% III 24-59% IV <5% |
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Colorectal Cancer Screening
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Colonoscopy
Flexible Sigmoidoscopy Fecal Occult Blood (FOBT) Fecal immunochemical test (FIT) Double-Contrast Barium Enema Virtual colonoscopy Molecular testing Stool DNA tests |
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When should screening begin?
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Beginning at age 50, both men and women should follow one of the following options:
Colonoscopy every 10 years Yearly FOBT + Sigmoidoscopyevery 5 years* Sigmoidoscopyevery 5 years* Double-contrast barium enema every 5 years* High-risk patients should begin screening earlier with colonoscopy African Americans should begin at age 45 If one 1stdegree or two 2nddegree relatives, begin at 40yo or 10 years before earliest diagnosis Repeat q 3-5 years If IBD, begin 8-10 years after symptom onset Repeat q 1-2 years |
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Colorectal Screening: why not?
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Bowel preps
Concern over adequate analgesia Lack of perceived risk Embarrassment Access to care |
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Bowel Preps
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Oral gastrointestinal lavage solutions
Polyethylene glycol (PEG) +/-bisacodyl Saline laxatives Sodium phosphate Caution in renal impairment Usually with bisacodyl Clear liquid diet 24h prior |
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Breast Cancer Screening
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Stage at Diagnosis
5-yearSurvival 0-I 100% II 86% III 57% IV 20% |
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Breast Cancer Screening Recommendations
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NCCN Breast Cancer Screening and Diagnosis Guidelines v.1.2010
Breast awareness All women starting at 20yo Clinical breast exam Q 1-2 years starting at 20yo Annually starting at 40yo Every 6-12 months if high-risk Annual mammogram All women starting at 40yo High-risk women starting at 35yo If familial history, starting at 25yo or 5-10 years before diagnosis Annual MRI High-risk women |
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Mammogram Controversy
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US Preventative Services Task Force
“The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start…should be an individual one and take patient context into account, including the patient’s values regarding specific benefits and harms.” Still recommended by American Cancer Society, National Cancer Institute and National Comprehensive Cancer Network |
