Anti Neoplastics

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dvb69339
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38596
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Anti Neoplastics
Updated:
2010-09-30 23:28:05
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Chemodrugs
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HO-Lectures 43-45
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  1. What are 3 things associated with tumor growth?
    • Loss of Contact inhibition
    • Lack of adhesion
    • Unable to differentiate fully
  2. Why do noncycling quiescent cells (low growth fraction) increase from early stage to late stage tumor?
    Probably because they do not have enough blood supply
  3. Explain the log-kill Hypothesis.
    As time progresses with a tumor, the number of cancer cells in the tumor increases exponentially. Many treatments kill 99.9% of all tumor cells. However then you must allow time to recover. Early tumors kills 99.9% and leaves a handful of cells. Treatment in late tumors kills 99.9% of all tumor cells and leaves 10^6 cells.
  4. What causes the resistance to drug treatment in cancer?
    • Heterogeneity of tumor with different cell types
    • Low growth fraction
    • Spontaneous mutation
    • Activity of P-glycoprotein
    • Increase in activity of topoisomerase I and II
  5. What is the philosophy for combination therapy in cancer?
    We can get different MOA and a greater effect of killing, but no increase in side effects.
  6. What was the first combination therapy in use for cancer?
    • MOPP for Hodgkin's Lymphoma
    • mechlorethamin
    • vincristine (Oncovin)
    • procarbazine
    • prednisone
  7. ABVD Combination Drug Regime
    • For Hodgkin's Lymphoma
    • doxorubicin (Adriamycin)
    • bleomycin
    • vinblastine
    • dacarbazine
  8. CHOP
    • For Lymphomas
    • cyclophosphamide
    • doxorubicin
    • vincristine (Oncovin)
    • prednisone
  9. What are common side effects for AntiNeoplastics?
    • Anything that uses rapidly cycling cells:
    • BM: Leukopenia, Thrombocytopenia, Anemia
    • GI TRACT: Stomatitis, intestinal ulceration, diarrhea, N/V
    • HAIR FOLLICLES: Alopecia
    • GONADS: Menstrual irregularities, impaired spermatogenesis
    • WOUNDS: Impaired healing
    • FETUS: Teratogenesis
  10. What are specific side effects for certain drugs?
    • Ototoxicity
    • Cardiotoxicity
    • Radition Recall
    • Pulmonary toxicity
    • Renal toxicity
    • Hyperuricemia
    • Peripheral neuropathy
  11. What is the major target of Alkylating Agents?
    DNA, specifically guanine, but also adenosine and cytosine
  12. What are the MOAs for Alkylating agents?
    • Cross linking
    • mispairing
    • depurination
    • ring cleavage
  13. How can cells develop resistance to alkylating agents?
    • Increase P-glycoprotein
    • Increase in competing nucleophiles, such as cysteine
    • Increase in DNA repair enzymes
  14. Mechlorethamine
    • 1st Alkylating Agent indicated in HL and NHL
    • IV, NOT PO
    • UNSTABLE: Mixed with H20 immediately prior to IV
    • A Vesicant
    • SE: N/V, acute myelosuppression, teratogenic, repro organ inhibition
  15. Chlorambucil
    • Alkylating Agent indicated in CLL
    • More stable, longer half-life, and PO in comparison to mechlorethamine
    • SE: N/V, myelosuppression, risk of AML
  16. Melphalan
    • Alkylating Agent indicated in myeloma, ovarian, and breast cancer
    • More stable, longer half-life, and PO in comparison to mechlorethamine
    • SE: mild N/V, myelosuppression, risk of AML
  17. Cyclophosphamide and Ifosfamide
    • Common alkylating agent PRO DRUG indicated in HL, NHL, ALL, AML, CLL, CML, multiple myeloma, breast, lung, ovary, and severe RA
    • Longest 1/2 life of mustards (7hrs.) given IV or PO, but ifosfamide is only IV
    • Side effects include: BM depression, N/V, alopecia, hemorrhagic cystitis caused by toxic metabolite acrolein (counter with MESNA), amenorrhea, immunosupressant
  18. Carmustine and Lomustine
    • MOA: alkylate and carbamoylate (destroys proteins)
    • Both ARE GREAT FOR PASSING BBB
    • Indicated in brain tumors (obviously), HL, NHL, colorectal cancer, multiple myeloma
    • SE: N/V, pulmonary toxicity, BM suppression
  19. Dacarbazine
    • Non-classical Alkylating agent
    • MOA: metabolite is non specific cell-cycle alkylating agent; A PRO DRUG!!!!
    • Indicated in HL, melanoma, and sarcomas
    • SE: N/V, myelosuppression, teratogenic, repro organ sensitive
  20. Temozolomide
    • Non-classical alkylating agent
    • MOA: metabolite acts as a non-specific cell cycle alkylating agent; A PRO DRUG!!! ALSO VERY LIPOPHILIC
    • Indicated in Brain tumors, malignant gliomas
    • SE: N/V, myelosuppression, teratogenic, repro-organ sensitive
  21. Bendamustine
    • A non-classical alkylating agent
    • MOA: alkylating agent that inhibits mitotic checkpoints and induces mitotic catastrophe
    • Indicated in CLL and NHL
    • SE: N/V, myelosuppression, hypersensitivity
  22. Platinum Coordinating Complexes
    • Cisplatin, carboplatin, oxaliplatin
    • MOA: Pt-guanine DNA crosslinking; inhibits DNA/RNA polymerase
    • Indications: Testicular cancer, head and neck cancer, ovarian cancer, small-lung cancer, colon cancer
    • SE: N/V, renal toxicity, ototoxicity, peripheral neuropathy, BM suppression (oxaliplatin is the least of these) (cisplatin the worst expect BM suppression---it's ok with that)
  23. What are the antimetabolite chemotherapy drug categories?
    • Folic Acid inhibitors
    • Purine Analog
    • Pyrimidein Analog
  24. Methotrexate
    • Folic Acid Analog (similar structure to dihydrofolate, tetrahydrofolate, and N5,N10-methylene-tetrahydrofolate)
    • MOA: inhibit dihydrofolate reductase, resulting in reduction of one carbon transfers (needed for de novo synthesis of DNA)
    • Indicated in oropharyngeal tumors, choriocarcinoma, acute childhood leukemia, acute psoriasis, rheumatoid arthritis, corticosteroid-dependent asthma, and immunosupressive agent/abortifiacient
    • SE: BM, GI, renal toxicity (fixed by hydration and alkalinization), neurotoxicity, liver, Radiation Recall

    Leucovorin is often administered with this drug
  25. Pemetrexed
    • Antifolate analog what is indicated for mesothelioma, non-small cell lung cancer
    • MOA: targets mainly thymidylate synthetase, DHFR and enzymes involved in purine synthesis (GARFT and AICARFT)
    • SE: myelosuppression, rash, mucositis, diarrhea
    • Requires Folic Acid and V B12 to reduce toxicities
  26. 5 fluorouracil (5-FU)
    • A pyrimidine analog which is converted to fdUMP which inhibits thymidylate synthetase
    • Indicated in solid tumros, breast cancer,carcinomas of GI tract
    • skin keratosis/psoriasis
    • SE: GI disturbances, myelosuppression, cerebellar ataxia, alopecia
    • Leucovorin enhances the activity of 5-FU by stabalizing thymidylate synthetase a moer stable complex
  27. Capecitabine
    • PO Prodrug of 5-FU indicated in metastatic breast cancer
    • SE: N/V, diarrhea, less myelosuppression than 5-FU, no alopecia
  28. Cytarabine
    • A cytosine molecule attached to an arabinose sugar (instead of deoxyribose sugar) that needs to be activated by addition of 3 phosphate groups
    • Drugs are deactivated by deaminase activity/Activated by kinase activity
    • Indicated for AML, ALL, CML
    • SE: myelosuppression, GI disturbances, stomatits
  29. Gemcitabine
    • Similar to cytarabine
    • MOA: inhibits DNA polymerase and ribonucleotide reductase
    • IT can not be deactivated by deaminases, so longer 1/2 life
    • Indicated in solid tumors, non-small cell cancer of the lung, pancreatic cancer
    • SE: well tolerated, myelosuppression, N/V
  30. Describe Purine Salvage Pathway
    Phosphoribosyl pryophosphate (PRPP) +Purine Base -----> purine ribonucleotide

    With the help of HGPRT (hypoxanthine guanine phosphoribosyl transferase)

    Hypoxanthine + PRPP-------------->inosinate------------->AMP/GMP
  31. 6-Mercaptopurine (6-MP)
    • hypoxamine analog which causes the formation of 6-TIMP (instead of inosinate)
    • Indicated for ALL, CML
    • SE: myelosuppression, GI

    Metabolized by xanthine oxidase (allopurinol inhibits, thus increasing 6-MP effect)
  32. azathiopurine
    • Prodrug for 6-Mercaptopurine
    • Indicated for immunosuppression and/or RA
    • Metabolized by TMPT (genetic problems can effect this)
  33. 6-thioguanine
    • an analog of guanine
    • MOA: competes for HGPRT (and PRPP) and damages DNA after incorporation/inhibits synthesis of AMP/GMP
    • ISNOT metabolized by Xanthine Oxidase so not affected by Allopurinol like 6-mercaptopurine is
  34. Fludarabine
    • Analog of adenosine
    • MOA: converted to 2-fluoro-ara-ATP and inhibits DNA polymerase and ribonucleotide reductase
    • Indicated in CLL
    • SE: BM depression, N/V, neurological problems
  35. Cladribine
    • Analog of deoxyadenosine (with Cl-)
    • MOA: activated by phosphorylation and incorporated into the DNA, it inhibits DNA synthesis and repair, and induces DNA strand breaks
    • Resistant to deaminase
    • Indicated in Hairy cell leukemia
    • SE: myelosuppression, nephrotoxicity, neurotoxicity
  36. Hydroxyurea
    • MOA: inhibits ribonucleotide reductase thus inhibiting DNA synthesis
    • Indications: CML, solid tumors, sickle cell anemia, psoriasis
    • SE: BM depression, stomatitis, GI ulceration, skin (hyperpigmentation and hyperkaratosis), radiation sensitizer, radiation recall
  37. Vinblastine, vincristine, vinorelbine
    • NATURAL PRODUCTS
    • MOA: disruption of MT in mitosis, thus inhibiting mitosis phase of the cell cycle
    • Indications: HL, choriocarcinoma, testicular cancer, ALL, non-small-lung cancer
    • SE: SEVERE vesicants, neurotoxicity (especially vincristine), alopecia, BM (especially vinblastine and vinorelbine)
  38. Paclitaxel, nanoparticle albumin bound (NAB) paclitaxel, docetaxel
    • TAXANES
    • MOA: build up of microtubules
    • Indications: Breast, Ovary, Head and Neck, Lung
    • SE: myelosuppression, peripheral neuropathy, hypersensitivity, fluid retention (Docetaxel)
  39. Etoposide
    • Epipodophyllotoxins
    • Inhibit Topoisomerase II DNA repair enzymes
    • Indicated in testicular cancer, small cell lung cancer episode
    • SE: BM, GI, vesicants, secondary leukemia, radiation recall
  40. Topotecan and Irinotecan
    • Camptothecins
    • MOA: bind to Topoisomerase I complexes
    • Indication: small lung cell cancer, metastatic cancer of ovary, colon, rectum
    • SE: Diarrhea, myelosuppression
  41. What are the cell cycle non-specific antibiotics?
    • Anthracenes:
    • doxorubicin, doxorubicin-liposomal, daunorubicin, idarubicin, epirubicin
    • MOA: intercalates DNA and binds Topoisomerase II
    • SE: discolors urine RED, cardiotoxin reaction, myelosuppression, GI, radiation recall
    • Indications: ALL, AML, Breast Cancer (epirubicin)
  42. Bleomycin
    • a glycopeptide
    • MOA: binds DNA and forms a complex with iron which breaks the DNA
    • SE: pulmonary fibrosis, pulmonary toxicity, NO BM TOXICITY
    • indicated for: Ovarian and Testicular cancer
  43. L-asparaginase
    • enzyme
    • MOA: Destroys asparagine needed to make aspartic acid which limits protein synthesis....
    • Indicated in ALL
    • SE: hypersensitivity, CNS neurotoxicity, fever, liver and kidney failure, pancreatitis, excessive NH3, coagulation deficiencies
    • IT DOESNOTCAUSE BM, GI, HAIR FOLLICLE PROBLEMS!!!!!!!!!
  44. Arsenic Trioxide
    • MOA: induces differentiation of promyelocitic leukemia cells and induces apoptosis
    • Indications: APL if tretinoin or anthracyclin did not work
    • SE: rash, N/V, tachycardia, QT prolongation, (ventricular arrhythmia)
  45. Tretinion All Trans retionic Acid (ATAR)
    • MOA: induces APL cells to normal by binding nuclear receptor and affecting transcription
    • Indicated in APL with no success with anthracyclin
    • SE: Vitamin A toxicity, fever, skin dryness, rash, CNS toxicities, teratogenic
  46. Prednisone, dexamethasone
    • toxic to lymphocytes
    • works through glucocorticoid receptors to induce apoptosis
    • SE: cushing's syndrome; also must withdraw slowly to prevent renal insufficiency
  47. cetuximab
    • monoclonal antibody that inhibits EGFR
    • often combined with irinotecan
    • SE: severe infusion reaction, instertial lung dz
  48. pantitumumab
    • same as cetuximab but fully human AB instead of chimeric
    • less SE
  49. gefitinib, erlotinib
    • UNDER GO CYP3A4 metabolism
    • inhibitor of EGFR-TK
    • only increase survival, donot cure :(
    • SE: NO PREG, GI perforation, prior radiation
  50. imatinib
    • MOA: competitive inhibitor of ATP binding site on c-abl, c-KIT, and PDGFR tyrosine kinase
    • Indicated in CML
    • SE: typical
  51. Nilotinib
    • like imatinib, but higher affinity
    • Indicated for all imatinib R CMLs except T315I mutation
  52. Dasatinib
    • Like Nilotinib
    • HIGHER MYELOSUPPRESSION
  53. Sorafenib, sunitinib
    • MOA: inhibits phosphorylation of tyrosine kinases
    • Indication: Advanced Renal Cell Carcinoma
    • SE: Rash, GI, hand and foot syndrome, hypertension
    • METABOLIZED BY CYP3A4

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