Canc2

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Canc2

  1. 1. Cancer Chemotherapy-2 Dr. R. Senthil Kumar
  2. 2. Classification
  3. 3. Alkylating agents <ul><li>Cyclophosphamide </li></ul><ul><li>Cisplatin </li></ul><ul><li>Procarbazine </li></ul><ul><li>Busulfan </li></ul><ul><li>Mechlorethamine </li></ul>
  4. 4. MOA <ul><li>Alkylating agents </li></ul>
  5. 5. Alkylating Agents- Used in wide variety of hematologic and solid tumors <ul><li>Thiotepa – ovarian cancer </li></ul><ul><li>Busulfan – DOC in CML (***Important ADR-Pulmonary fibrosis). </li></ul><ul><li>***Nitrosoureas (Carmustine and lomustine ) - brain tumors </li></ul><ul><ul><li>Highly lipid soluble drugs hence reach high concentration in the brain and CSF. </li></ul></ul><ul><li>Streptozocin – insulin-secreting islet cell carcinoma of the pancreas </li></ul><ul><li>Mechlorethamine – Prodrug. C omponent of MOPP regimen for Hodgkin’s disease. It is a highly irritant drug so care should be taken to avoid extravasation during IV administration </li></ul><ul><li>Chlorambucil (Leukeran): DOC for CLL. Slow acting and least toxic nitrogen mustard. </li></ul>
  6. 6. Cyclophosphamide <ul><li>It is a prodrug and is activated by the P-450 enzymes to its active form phosphoramide mustard </li></ul><ul><li>The active drug alkylates nucleophilic groups on DNA bases </li></ul><ul><ul><li>Particularly at the N-7 position of guanine </li></ul></ul><ul><li>This leads to cross linking of bases, abnormal base pairing and DNA strand breakage </li></ul>
  7. 9. Mechanism of resistance <ul><li>*** The mechanisms mentioned below are common for all the alkylyting agents </li></ul><ul><li>Increased DNA repair </li></ul><ul><li>Decreased drug permeability </li></ul><ul><li>Production of “trapping” agents (thiols) </li></ul>
  8. 10. Uses <ul><li>Non-Hodgkin’s lymphoma </li></ul><ul><li>Breast Ca </li></ul><ul><li>Ovarian Ca </li></ul><ul><li>Neuroblastoma </li></ul>
  9. 11. ADR <ul><li>Acrolein is the metabolite </li></ul><ul><li>Responsible for causing hemorrhagic cystitis </li></ul><ul><ul><li>Suprapubic pain </li></ul></ul><ul><ul><li>Hematuria </li></ul></ul><ul><ul><li>Cyctoscopic findings </li></ul></ul><ul><li>***This is prevented/treated by MESNA (mercaptoethanesulfonate) </li></ul><ul><li>Rarely cyclophosphamide can cause SIADH and pulmonary toxicity </li></ul>
  10. 13. Cisplatin <ul><li>Platinum analog </li></ul><ul><li>Same MOA as cyclophosphamide </li></ul><ul><li>**Used in testicular carcinoma </li></ul><ul><li>Also used for Ca of bladder, lung and ovary </li></ul><ul><li>Carboplatin is new drug with better safety profile </li></ul><ul><li>ADR </li></ul><ul><li>Nephrotoxicity (prevented by Amifostine***) </li></ul><ul><li>***Ototoxicity (acoustic nerve damage) </li></ul><ul><li>Peripheral neuritis </li></ul><ul><li>Severe nausea and vomiting </li></ul>
  11. 14. Procarbazine <ul><li>MOA: forms hydrogen peroxide, which generates free radicals that cause DNA damage </li></ul><ul><li>Important component of regimens especially for Hodgkin’s lymphoma </li></ul><ul><li>ADR </li></ul><ul><li>***Disulfiram like reactions </li></ul>
  12. 15. Blood in the urine!!! <ul><li>A 30-year-old man is seen at the ER complaining about severe suprapubic pain, fever and signs of passing blood in the urine. He is currently in treatment for non-Hodgkin’s lymphoma (four drug regimen). </li></ul><ul><li>What is your preliminary diagnosis? </li></ul><ul><li>If it is drug induced, who is “the culprit”? </li></ul><ul><li>What is the mechanism behind the latest complication? </li></ul><ul><li>How to treat the complication? </li></ul><ul><li>Which drug we covered until now has serious nephrotoxic effects? </li></ul><ul><li>How to prevent that particular drug induced renal damage? </li></ul><ul><li>ADR of: </li></ul><ul><ul><li>Procarbazine </li></ul></ul><ul><ul><li>Busulfan </li></ul></ul>
  13. 16. Legend Drug Class Sub-class Prototype Drug Trimetrexate Pemetrexed Thioguanine Fludarabine Phosphate Cladribine Cytarabine Gemcitabine Capecitabine Antimetabolites Folic Acid Analogs Purine Analogs Pyrimidine Analogs Methotrexate Mercaptoguanine Fluorouracil
  14. 17. Antimetabolites <ul><li>They are structurally similar to endogenous compounds </li></ul><ul><li>They act as antagonists of: </li></ul><ul><ul><li>Folic acid (methotrexate) </li></ul></ul><ul><ul><li>Purines (Mercaptopurine and thioguanine) </li></ul></ul><ul><ul><li>Pyrimidine (fluorouracil, cytarabine) </li></ul></ul>
  15. 18. Antimetabolits: sites of drug action
  16. 19. Methotrexate
  17. 20. Methotrexate (MTX) <ul><li>MTX is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR) </li></ul><ul><li>Thus it interferes with the synthesis of tetrahydrofolate (THF) </li></ul><ul><li>THF serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. </li></ul><ul><li>Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins. </li></ul>
  18. 21. Mechanism of Resistance 1. Decreased drug transport 2. Altered DHFR 3. Decreased polyglutamate formation 4. Increased levels of DHFR
  19. 22. Contd.. <ul><li>Most commonly used anticancer drug. </li></ul><ul><li>Cell cycle specific (CCS) drug and acts during S phase of the cell cycle. </li></ul><ul><li>Antineoplastic, immunosuppressant and antiinflammatory </li></ul><ul><li>Used in RA, psoriasis </li></ul><ul><li>Well absorbed orally; can also be given IM, IV or intrathecally**. </li></ul><ul><li>It is bound to plasma proteins, does not cross the BBB and most of the drug is excreted unchanged in urine. </li></ul><ul><li>It is a weak acid and so is excreted better at high urine pH. Appropriate hydration and alkalinizing the urine is important to prevent renal tox with MTX </li></ul>
  20. 23. ADR <ul><li>Bone marrow suppression (BMS) </li></ul><ul><li>Mucositis </li></ul><ul><li>Folic acid deficiency </li></ul><ul><li>The toxic effects of MTX on normal cells is reduced by administering folinic acid (leucovorin) </li></ul><ul><ul><li>This is called leucovorin rescue **** </li></ul></ul><ul><ul><li>Higher the dose of MTX more the leucovorin you give** </li></ul></ul>
  21. 24. Leucovorin Rescue <ul><li>Mechanism of action of methotrexate and the effect of administration of leucovorin. </li></ul><ul><li>FH2 = dihydrofolate </li></ul><ul><li>FH4 = tetrahydrofolate </li></ul><ul><li>dTMP = deoxythymidine monophosphate </li></ul><ul><li>dUMP = deoxyuridine mono phosphate. </li></ul>
  22. 25. 6-Mercaptopurine (6-MP) & Thioguanine <ul><li>Both 6-MP and Thioguanine are activated by HGPRT to toxic nucleotides that inhibit several enzymes involved in purine metabolism </li></ul><ul><li>***Resistance is due to cancer cells having  d activity of HGPRT </li></ul><ul><li>Cancer cells also  es alkaline phosphatase that inactivate toxic nucleotides </li></ul>
  23. 26. 6-MP & Allopurinol <ul><li>6-MP is metabolized in the liver by xanthine oxidase and the inactive metabolites are excreted in the urine </li></ul><ul><li>***Allopurinol is used frequently to treat/prevent hyperuricemia caused by many anticancer drugs. </li></ul><ul><li>If Allopurinol is used with 6-MP then the dose of 6-MP is reduced by more than 75% </li></ul><ul><ul><li>Why?? </li></ul></ul>
  24. 27. Cytarabine (Ara-C) <ul><li>Cytarabine arabinoside is a pyrimidine antimetabolite </li></ul><ul><li>The drug is activated by kinases to AraCTP </li></ul><ul><ul><li>This acts as an inhibitor of DNA polymerase </li></ul></ul><ul><li>***of all antimetabolites, this is the most specific for S phase of tumor cell cycle </li></ul><ul><li>It is an important component in acute lukemia regimens </li></ul><ul><li>ADR: at high doses cause neurotoxicity (cerebellar dysfunction and peripheral neuritis) </li></ul><ul><ul><li>Hand-foot syndrome*** </li></ul></ul>
  25. 28. 5-FU <ul><li>Mechanism of the cytotoxic action of 5-FU </li></ul><ul><li>5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. </li></ul><ul><li>5-FU = 5-fluorouracil </li></ul><ul><li>5-FUR = 5-fluorouridine </li></ul><ul><li>5-FUMP = 5-fluorouridine monophosphate </li></ul><ul><li>5-FUDP = 5-fluorouridine diphosphate </li></ul><ul><li>5-FUTP = 5-fluorouridine triphosphate </li></ul><ul><li>dUMP = deoxyuridine monophosphate </li></ul><ul><li>dTMP = deoxythymidine monophosphate </li></ul><ul><li>5-FdUMP = 5-fluorodeoxyuridine monophosphate. </li></ul>
  26. 29. Contd.. <ul><li>5-FU causes, “thymidineless death” of cells </li></ul><ul><li>Resistance is due to  d activation of 5-FU and  d thymidylate synthase activity </li></ul><ul><li>Uses and ADR </li></ul><ul><li>Metastatic carcinomas of the breast and the GI tract, hepatoma </li></ul><ul><li>Carcinomas of the ovary, cervix, urinary bladder, prostate, pancreas, and oropharyngeal areas </li></ul><ul><li>Combined with levamisole for Rx of colon cancer </li></ul><ul><li>ADR: nausea, mucositis, diarrhea, *** hand and foot syndrome , Alopecia, hyperpigmentation, neurologic deficits, bone marrow depression </li></ul>
  27. 30. Megaloblastic anemia <ul><li>A 50-year-old man is undergoing chemotherapy with a multi-drug regimen after being diagnozed to have a malignant tumor. Soon after the first cycle of chemotherapy, he develops symptoms of severe fatigue and pallor. His Hb is very low and the peripheral smear shows presence of megaloblasts. </li></ul><ul><li>What is your prelim. Diagnosis? </li></ul><ul><li>Which of the drugs we discussed can be most likely responsible for this complication? </li></ul><ul><li>Which compound (and how) administered soon after chemotherapy could have prevented the toxicity? </li></ul><ul><li>Which are the anticancer drugs which can cause tingling, feeling of warmth, redness, flaking and blisters (what is this)? </li></ul><ul><li>MOA and Mech of resistance to 6-MP and TG? </li></ul><ul><li>MOA of 5-FU </li></ul>
  28. 32. Vinblastine Vincristine Vinorelbine Teniposide Irinotecan Docetaxel Plant Alkaloids Vinca Alkaloids Podophyllotoxins Camptothecins Taxanes Vinblastine Etoposide Topotecan Paclitaxel
  29. 33. Vinka alkaloids (Vinblastine, vincristine) <ul><li>These drugs block the formation of mitotic spindle by preventing the assembly of tubulin dimers into microtubules </li></ul><ul><li>***They act primarily on the M phase of cancer cell cycle </li></ul><ul><li>Resistance is due to  d efflux of drugs from tumor cells </li></ul>
  30. 34. Vinka alkaloids (animation and ADR) <ul><li>Microtubule Synthesis animation </li></ul><ul><li>Inhibition of spindle function </li></ul><ul><li>ADR </li></ul><ul><li>Severe neurotoxicity </li></ul><ul><ul><li>Paresthesias </li></ul></ul><ul><ul><li>Loss of reflexes </li></ul></ul><ul><ul><li>Foot drop </li></ul></ul><ul><ul><li>Ataxia </li></ul></ul>
  31. 35. V in B lastine V in C ristine (oncovan) Uses ; (ABVD) Hodgkin’s disease Lymphomas Carcinoma B reast Testicular tumors Toxicity: B one marrow suppression, anorexia, nausea, vomiting & Diarrhea, Alopecia Uses : (MOPP) C hildhood leukemias C hildhood tumors-Wilm’s tumor, Neuroblastoma, Hodgkin’s disease Toxicity: Peripheral neuritis with Paresthesia, Muscle weakness ***Vincristine has marrow sparing effect
  32. 36. Etoposide & Teniposide <ul><li>Acts by inhibiting topoisomerase II </li></ul><ul><li>These drugs are most active in late S and early G2 phase </li></ul><ul><li>Used in combination Tx of small cell carcinoma of lung, prostrate and testicular carcinomas </li></ul><ul><li>Other topoisomerase inhibitors: </li></ul><ul><li>Topotecan, Irinotecan </li></ul><ul><ul><li>Both act by inhibiting topoisomerase-I </li></ul></ul>
  33. 37. Topoisomerase inhibitors
  34. 38. Paclitaxel & Docetaxel <ul><li>These drugs act by interfering with mitotic spindle </li></ul><ul><li>They prevent micotubule disassembly into tubulin monomers </li></ul><ul><li>Taxanes animation </li></ul><ul><li>ADR </li></ul><ul><li>Neutropenia </li></ul><ul><li>Peripheral neuropathy </li></ul>
  35. 39. Questions <ul><li>What is the diff between MOA of taxanes and Vinca alkaloids </li></ul><ul><li>Which is the marrow sparing anticancer drug </li></ul><ul><li>Topoisomerase-1 inhibitors </li></ul><ul><li>Topoisomerase-2 inhibitors </li></ul>
  36. 40. Anticancer Antibiotics <ul><li>Anthracyclines: </li></ul><ul><ul><li>Doxorubicin (Adriamycin) </li></ul></ul><ul><ul><li>Daunorubicin </li></ul></ul><ul><li>Bleomysin </li></ul><ul><li>Dactinomycin </li></ul><ul><li>Mitomycin </li></ul>
  37. 41. Doxorubicin & Daunorubicin <ul><li>These drugs intercalate between base pairs, inhibit topoisomerase II and also generate free radicals </li></ul><ul><li>They block RNA and DNA synthesis and cause strand scission </li></ul><ul><li>*These are CCNS drugs </li></ul><ul><li>Used as a component in ABVD regimen in Hodgkin’s lymphoma </li></ul>
  38. 42. ADR <ul><li>Cardiac toxicity (due to generation of free radicals) </li></ul><ul><li>Acute form: arrthythmias, ECG changes, pericarditis, myocarditis </li></ul><ul><li>Chronic form: *** Dilated cardiomyopathy , heart failure </li></ul><ul><li>****Rx with dexrazoxane </li></ul><ul><ul><li>This is an inhibitor of iron mediated free radical generation </li></ul></ul><ul><li>Bone marrow depression, Total alopecia </li></ul><ul><li>Radiation recall reaction </li></ul>
  39. 43. Bleomycin <ul><li>Acts through binding to DNA , which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis </li></ul><ul><li>The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations </li></ul><ul><li>CCS drug that causes accumulation of cells in G 2 </li></ul><ul><li>Uses </li></ul><ul><li>ABVD regimen for Hodgkin’s </li></ul><ul><li>Intracavitary therapy in ovarian and breast cancers ( Sclerosing agent ) </li></ul><ul><li>ADR </li></ul><ul><li>***Pulmonary fibrosis </li></ul>
  40. 44. Questions <ul><li>ADR of anthracyclines? (clinical symptoms) </li></ul><ul><li>Why ADR with anthracyclines? </li></ul><ul><li>How to treat it? </li></ul><ul><li>ADR of bleomycin? </li></ul>
  41. 45. Hormonal agents <ul><li>Glucocorticoids </li></ul><ul><li>Sex hormone antagonists </li></ul><ul><li>GnRH analogs </li></ul><ul><li>Aromatase inhibitors </li></ul>
  42. 46. Glucocorticoids (Prednisone) <ul><li>Because of their marked lympholytic action, they are used in acute leukemias and lymphomas. </li></ul><ul><li>Have anti-inflammatory effect </li></ul><ul><li>Increase appetite </li></ul><ul><li>Produce euphoria (feeling of well being) </li></ul><ul><li>Increase body weight </li></ul><ul><li>Suppress hypersensitivity reaction due to certain anticancer drugs </li></ul><ul><li>Control hypercalcemia </li></ul><ul><li>Control bleeding </li></ul><ul><li>Have non-specific antipyretic effect </li></ul><ul><li>Increase the antiemetic effect of ondansetron/granisetron/ metoclopramide </li></ul>
  43. 47. Sex hormone antagonists
  44. 48. Tamoxifen <ul><li>It is a SERM </li></ul><ul><li>Blocks the binding of estrogen to receptors of estrogen sensitive cancer cells in bresat tissue </li></ul><ul><li>It is used in receptor positive breast carcinoma </li></ul><ul><li>Also useful in progestin resistant endometrial carcinoma </li></ul><ul><li>ADR: </li></ul><ul><li>Hot flushes, vaginal bleeding and venous thrombosis </li></ul><ul><li>Other drugs </li></ul><ul><li>Flutamide: androgen receptor antagonist used in prostatic carconima </li></ul><ul><li>ADR for flutamide includes: gynecomastia, hot flushes </li></ul>
  45. 49. MOA of drugs
  46. 50. GnRH analogs <ul><li>Leuprolide, gosarelin and naferelin </li></ul><ul><li>Effective in management of Prostatic carcinomas </li></ul><ul><li>When given in constant doses they inhibit release of pituitary LH and FSH </li></ul><ul><li>These drugs suppress gonadal function due to down regulation and desensitization of Gn-RH receptors </li></ul><ul><li>ADR </li></ul><ul><li>Leuprolide may cause gynecomastia, hematuria, impotence and testicular atrophy </li></ul>
  47. 51. Aromatase inhibitors <ul><li>The aromatase reaction is responsible for the extra-adrenal synthesis of estrogen from androstenedione </li></ul><ul><li>This takes place in liver, fat, muscle, skin, and breast tissue, including breast malignancies. </li></ul><ul><li>Peripheral aromatization is an important source of estrogen in postmenopausal women. </li></ul><ul><li>Aromatase inhibitors decrease the production of estrogen in these women. </li></ul>
  48. 52. Contd..
  49. 53. Contd.. <ul><li>Anastrozole and Letrozole </li></ul><ul><li>These drugs inhibit the aromatase enzyme </li></ul><ul><li>**** Used in Tx of postmenopausal women with metastatic breast ca (1 st line drug) </li></ul><ul><li>ADR includes: bone pain and peripheral edema </li></ul>
  50. 54. Miscellaneous agents Asparaginase, imatinib, interferons, monoclonal antibodies
  51. 55. Asparaginase <ul><li>L-Asparaginase catalyzes the deamination of asparagine to aspartic acid and ammonia. </li></ul><ul><li>L-Asparaginase is used in combination therapy to treat childhood acute lymphocytic leukemia </li></ul><ul><li>Its mechanism of action is based on the fact that some neoplastic cells require an external source of asparagine because of their limited capacity to synthesize sufficient amounts of that amino acid to support growth and function. </li></ul><ul><li>L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesis </li></ul><ul><li>ADR </li></ul><ul><li>Acute pancreatitis***** </li></ul>
  52. 56. Contd..
  53. 57. Imatinib <ul><li>Example of a drug, whose development was guided by knowledge of a specific oncogene </li></ul><ul><li>Used for the treatment of chronic myeloid leukemia </li></ul><ul><li>Acts by inhibiting tyrosine kinase activity of the protein product of the Bcr-Abl oncogene </li></ul><ul><li>This gene is expressed in CML </li></ul>
  54. 58. MOA of imatinib <ul><li>Imatinib MOA </li></ul>
  55. 59. Interferons <ul><li>Human interferons have been classified into three types—α, β, and  —on the basis of their antigenicity. </li></ul><ul><li>The α interferons are primarily leukocytic, whereas the β and  interferons are produced by connective tissue fibroblasts and T lymphocytes, respectively. </li></ul><ul><li>Recombinant DNA techniques in bacteria have made it possible to produce two species designated interferon-α-2a and -2b used in Tx of neoplastic diseases. </li></ul><ul><li>***Interferon-α-2a is presently approved for the management of hairy-cell leukemia, chronic myeloid leukemia, and acquired immunodeficiency syndrome (AIDS)–related Kaposi sarcoma. </li></ul><ul><li>***Interferon-α-2b is approved for the treatment of hairy-cell leukemia, melanoma, AIDS-related Kaposi's sarcoma, and follicular lymphoma. </li></ul>
  56. 60. Monoclonal Antibodies <ul><li>They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. </li></ul><ul><li>The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type. </li></ul><ul><li>Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies. </li></ul><ul><li>Currently, several monoclonal antibodies are available in the United States for the treatment of cancer. </li></ul><ul><li>Trastuzumab, rituximab, bevacizumab, and cetuximab </li></ul>
  57. 61. Trastuzumab <ul><li>In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 % of patients. </li></ul><ul><li>Trastuzumab is a recombinant DNA–produced, humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity. </li></ul><ul><li>Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S phase. </li></ul>
  58. 62. FDA approved MAb
  59. 63. Questions??? <ul><li>What are Flutamide and Leuprolide and mention their uses? </li></ul><ul><li>MOA of tamoxifen? </li></ul><ul><li>MOA of anastrozole and letrozole? </li></ul><ul><ul><li>Important clinical indication for these drugs? </li></ul></ul><ul><li>Important ADR of L-asparaginase? </li></ul><ul><ul><li>Clinical symptoms of ADR (including lab) </li></ul></ul><ul><li>MOA and use of imatinib? </li></ul><ul><li>MABs used in cancer chemotherapy (know four of them circled above) </li></ul>
  60. 64. Treatment of Specific cancers <ul><li>Hodgkin’s disease: </li></ul><ul><li>ABVD regimen (doxorubicin,bleomycin,vinblastine,dacarbazine) </li></ul><ul><li>MOPP regimen (mechorethamine,vincristine,procarbazine,prednisone) </li></ul><ul><li>NHL: CHOP regimen (cyclophosphamide,doxorubicin,vincristine,prednisone) </li></ul><ul><li>Multiple myeloma : MP protocol (melphalan and prednisone) </li></ul><ul><li>Breast ca: </li></ul><ul><li>CMF protocol (cyclophosphamide-MTX-fluorouracil) </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Anastrozole, letrozole </li></ul>
  61. 65. Prevention/management of Cancer Chemotherapy induced ADR <ul><li>Nausea and vomiting : 5-Ht3 antagonist (ondansetron) </li></ul><ul><li>Bone marrow suppression : Filgrastim, Sargromastim (colony stimulating factors) </li></ul><ul><li>MTX toxicity : Leucovorin </li></ul><ul><li>Cyclophosphamide toxicity : MESNA </li></ul><ul><li>Cisplatin toxicity : Amifostine </li></ul><ul><li>Anthracycline toxicity ; Dexaroxazone </li></ul>

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