1. general info
   1. actions of cytoxic agents
      1. most are cytotoxic
         1. low therapeutic index
         2. dose often measured in mg/meters squared
         3. low selecivity
      2. N/V
         1. 5HT remaining in GI tract
         2. tx: target 5HT
            1. 5-HT3 blockers
            2. ondansetron (Zofran)
            3. p.o./ iv
            4. gramsetron (Kytril)
            5. po/iv
            6. dolasetron (Anzemet)
            7. iv
            8. palosetron ( Aloxi)
            9. iv
         3. older tx
            1. prochlorperazine (Compazine)
            2. po
            3. dronabinol (Marinol)
            4. po
            5. contains THC
            6. nabitone (Cesamet)
            7. analog of THC
            8. po
            9. metoclopramide (Reglan)
            10. stimulates gastric emptying
            11. D2R inhib
            12. aprepitant (Emend)
            13. synthetic cmpd
            14. neurokinin-1 receptor blocker
            15. given po before chemo & couple of days after
            16. iv
            17. not water soluble
            18. so you have the phosphoamide version aprepitant posphoamide
            19. pro-drug
            20. hydrolyzed in vivo
            21. fosaprepitant
            22. iv version
      3. bone marrow depression
         1. myelo depression -> inc incidence of infx and hemmorhage
      4. hyperuricemia
         1. occurs when a cell is killed (get DNA/RNA) --> purines--> oxidized into uric acid
         2. tx: urocosurics
            1. probenacid
         3. tx: xanthine oxidase inhib
            1. allopurinol
            2. febulostat (Uloric)
      5. immunosupression
         1. causes inc opportunistic infx
      6. alopecia
      7. carcinogenic
      8. teratogenic
      9. chemo also used in TB
   2. cancer
      1. contact inhibition is lost (they continue to grow on top of each other)
      2. oncogenes are "turned on" in cancer cells
2. alkylating agents
   1. mustard deriv
      1. liquid
         1. cytotoxic
         2. volatile
         3. abs rapidly when sprayed
         4. dec white blood cell count in war survivors
         5. used to tx leukemia by replacing "S" with "N"...less volatile
            1. nitro-mustards
            2. mechlovethaurias
            3. SE
            4. vesicant (causes blistering of the skin)
            5. not given often (severe bone marrow depression)
            6. 6 wks
            7. cyclophosphamide (Cytoxan)
            8. not alkylating agent bc it's a prodrug converted in vivo
            9. toxic metabolite acrolein
            10. 3A4/ 2D6 substrate
            11. not a vesicant
            12. for high doses give MESNA or hydrate pt
            13. 3L a day. day before -3 days after
            14. tx
            15. lymphoma, leukemia, breast cancer, ovarian cancer (hard to dx/tx), neuroblastoma, retino blastoma
            16. admin in AM
            17. po
            18. SE
            19. alopecia
            20. < bone marrow depression than mechlovethaurias
            21. hemmorhagic cystitis
            22. urotox- hematouria characteristic
            23. excrection of cytoxic products
            24. cardiotox in high doses > 15mg/m^2
            25. ifosfamide (Ifex)
            26. same MOA as cyclophasphamide
            27. MUST use with MESNA and hydration
            28. 60% of IFEX dose in 3 doses started when Ifex start
            29. tx
            30. testicular cancer
            31. SE
            32. hemmorhagic cystitis
            33. mesno
            34. highly ionized
            35. not excreted in urine
            36. has -HS group stays in blood and reacts w/ ctotoxic agents in blood then excreted in urine
            37. tx
            38. hemmorhagic cystitis
   2. nitrozourias
      1. urea gr makes unstable in alkaline (pH of 7.4)
      2. NO group is the alkalating species
      3. tx
         1. lipid soluble for brain tumors
      4. SE
         1. bone marrow depression --> seizures
            1. wait 6 ws between doses
      5. lomustine (Ceenu)
         1. po/iv
         2. enters CNS easily
      6. carmustine (Bienn)
         1. enters CNS easily
   3. platinum deriv
      1. bind to an alkylate DNA
      2. all given IV
      3. removal by renal excretion
      4. cisplatin (platinol)
         1. SE
            1. neurotox
            2. peripheral neuropathy- burning stinging, tingling
            3. nephrotox
            4. hydrate pt /mannitol
            5. Amifostine- expensive given as last resort
            6. GI tox -N?V
            7. bone marrow depression
            8. ototox
         2. for bladder cancer, testicular,ovarian tumors
         3. used in combo
      5. carboplatin (paraplatin)
         1. less nephro, neuro, and ototox
         2. fewer indications
            1. tx ovarian & lung cancer
         3. dose by calvart equation
            1. dose in mg= AUC*(25+crcl)
      6. oxaliplatin (Eloxatin)
         1. concerted by hydrolysis to non toxic metabolites then removed by renal excretion
         2. less toxic of all
         3. similar toxicities but lower incidence
         4. less severe
         5. persisant parasthesias
            1. activated by cold
            2. mostly in face
         6. used w/ 5-FU for colon cancer
   4. purine like analog
      1. temozolamide (Temodar)
         1. converted by hydrolysis to a triazine alkylating agent
         2. po/iv
         3. tx
            1. astrocytoma resist to nitrozorias
            2. glioblastomas
         4. SE
            1. bone marrow depression
3. anti-metabolities
   1. susbstance that compete/interfere with a normal metabolite in the bodys normal metab
   2. antifolate
      1. 5-Formyl THFA (Leucovorin)
         1. air stable
         2. can sub for 5,10-methylene THFA
         3. antidote for DHFA reductase blockers
            1. trimethaprim (blocks the DHFA reductase blocker)
         4. doesnt effect bacteria...only the human
      2. methotrexate (MTX)
         1. inhib of human DHFA reductase
         2. po/ iv/ intrathecal
         3. blocks DNA production in cancer cell to kill the cell
         4. folic acid deriv
         5. binds to plasma protiens (50%)
            1. can be displaced by NSAIDs, sulfonamides,tetracyclines, warfarin, phenytoin
         6. small therapeutic index
         7. elim by glomerular filtration/ tubular secretion
            1. tubular secretion blocked by NSAIDs/ probenacid/ penicillins
         8. cancer tx
            1. acute leukemia, lymphoma, breast cancer, lung, squamous cell, choriocarcinoma
            2. rescue therapy in bone cancer (give lethal dose, then rescue with leucovorin)
            3. with higher doses >1gm/m^2
            4. given 24 hrs after start of MTX inf
         9. non-cancer tx
            1. psoriasis
            2. RA
         10. tox
             1. hepato
             2. assoc w/ long term therapy
             3. diarheea
             4. stomatitus -severe hemmorhage
             5. bone marrow depression
             6. mucositis
         11. supplemental folic acid can reduce SE or can reverse therapeutics of it (?)
      3. pemetrexed (Alimta)
         1. inhibits DHFA reductase & thymidylate synthtase
         2. iv inf w/ cisplatin
         3. tx
            1. malignant pleuro mesothelioma
            2. non small cell lung cancer (NSCLC)
         4. SE
            1. erythematsus
            2. puritic rash
            3. pre-tx w/ dexamethasone
            4. neutropenia/sepsis
         5. req low dose daily folic acid /B-12 supplement
            1. tell pt not to eat food with excess folc acid i.e. green leafy veggies
         6. fairly new drug
   3. pyrimidine anti metabolites
      1. to be functional need to be converted to neucleotide in vivo
      2. 5-Flurouracil (5-FU) (Adrucile )
         1. inhib thymadilate synthetase
         2. used w/leucovorin to enhance affinity for thymadilate synthetase
         3. 1st drug used for solid tissues
         4. tx
            1. iv
            2. stomach, colon, breast cancer
            3. too polar to give po
            4. topically (Efudex)
            5. pre-malignant keratoses
            6. basal cell carcinomas
         5. leucovorin inc tox
            1. metab by fdump...in the presence of folates is more stable & binds to TS more tightly
         6. SE
            1. dose limiting tox dependent on administration
            2. bolus
            3. myelosupression
            4. contin inf
            5. gi related
            6. mucocytis (inflam of oral cavity)
            7. give ice chips b4 and during or Kepivance
            8. given voth ways to tx colon cancer
      3. capectitabine (Xeloda)
         1. pro drug converted in vivo to 5_FU
         2. can be admin po BID
         3. tx
            1. breast, colorectal
         4. SE
            1. assoc w/ hand foot syndrome
            2. pain, redness, blistering of palms/soles
            3. GI: diarrhea
            4. give immodium
      4. cytarabine (Ara-C)
         1. very myelosuppressive
            1. nadar (wbc) 7-14 days
         2. SE
            1. diarrhea (day 3)
            2. conjunctivitis
            3. give artificial tears/ steroid eye gtts
            4. neurotox
            5. ataxia, nystagmus
            6. >1gram/m^2
      5. gemcitabine
         1. given iv
         2. inhibits DNA biosynthesis
         3. tx
            1. ovarian, NSCLC
            2. unique bc 1st line tx for pancratic cancer
            3. sx-less until advanced
      6. azacytodine (Vidaza)
         1. SubQ/ iv
         2. incorporates w/ DNA chain and interferes w/ func of DNA
         3. tx
            1. myelodisplactic syndrome
            2. collection of bone marrow disorders (primary or secondary)
            3. primary -de novo spontaneous occurance
            4. secondary - radiation or chemo
            5. anemia leucopenia, thrombocytopenia
   4. purines
      1. not used much
      2. 6-mercaptopurine
         1. tx
            1. leukemia
         2. metab by xanthine oxidase
            1. inhib by allopurinol thus inc toxicity
4. natural products
   1. alkaloids
   2. antibiotics
5. microtubule targeting agents
   1. vinca alkaloids
      1. SE
         1. neuropathy
      2. interact with 3A4
      3. vincristine (Oncovin)
         1. SE
            1. peripheral neuropathy
            2. constipation
            3. SIADH
         2. max weekly dose od 2mg
      4. vinblastine
      5. vinorelbine
   2. taxanes
      1. Paclitaxel (Taxol)
         1. SE
            1. hypersensitivity rxns
            2. give benadryl/ decadron/ famotidine
            3. myelosupression
      2. nab-paclitaxol (Abraxane)
         1. tx
            1. taxol resistant cancers
         2. dec hypersensitivity rxns...can give higher doses
      3. docetaxol (Taxotere)
         1. SE
            1. peripheral edema
            2. decadron decreases incidence
   3. misc
      1. ixabepilone (Ixempa)
         1. (-) beta III tubulin subunit
         2. 3A4 substrate
         3. req pre-medications