Chemotherapy II
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- What are cell cycle specific drugs that work at S phase?
- Purine antimetabolites Antifolates Pyrimidine antimetabolites Ribonucleotide reductase inhibitors DNA polymerase inhibitors
- Is a topoisomerase II inhibitor a cell cycle specific drug?
- yes
- how does Epipodophyllotoxins work?
- topoisomerase inhibition
- which drugs work at m phase? how do they work?
- Vinca alkaloids Taxanes block mitotic spindle
- is a topoisomerase I inhibitor a cell cycle specific drug?
- no
- what does Camptothecins do to inhibit cell cycle?
- topoisomerase I inhibition
- is a dna crosslinker cell cycle specific chemotherapy?
- no
- how do Alkylating Agents Platinums work?
- dna crosslinker
- what type of chemotherapy is nitrogen mustards? name some examples of nitrogen mustards
- Alkylating Agents Nitrogen mustards Cyclophosphamide (Cytoxan) Mechlorethamine (Mustargen) Mephalan (Alkeran) Chlorambucil (Leukeran)
- what type of chemo is a Nitrosureas? name some examples
- alkylating agent Carmustine (BiCNU) Lomustine (CeeNU) Streptozocin (Zanosar)
- What type of chemotherapy agent is an ethylinimne? give an example of one type of drug
- Thiotepa (Thioplex)
- What type of chemotherapy is an alkyl sulfonate? give an example
- Alkyl sulfonates Busulfan (Myleran)
- What type of chemotherapy is triazine? give an example
- Triazines Dacarbazine (DTIC-Dome) Temozolamide (Temodal)
- What is the mechanism of action of alkylating agents?
- Transfers alkyl groups to a nucleophile (sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups on proteins or DNA) Bifunctional crosslinks to DNA that interfere with base pairing DNA strand breaks G2 cell cycle arrest
- What is the dose limiting toxicity of an alkylating agent?
- Myelosuppression
- What type of chemo is Cisplatin? and what it its dose limiting toxicity? mechanism of action?
- Platinum, nephrotoxicicty broad action agains solid tumors, esp squamous cell carcinoma
- What type of chemo is Carboplatin (Paraplatin)? dose lmiting toxicity and mechanism of action?
- Platinum myelosuppression dose limiting mechanism of action is a broad activity agains solid tumors
- what is the dose limiting toxicity of Oxaliplatin and what is its mechanism of action?
- 2nd string drug for colorectal cancer and it has neurotoxicity
- what is the general mechanism of action for platinums?
- Crosslinks N7 guanine on DNA - similar to alkylating agents
- What type of chemotherapy is folic acid? and give some examples
- Folic acid is an antimetabolite antagonists Methotrexate (Amethopterin) Ralitrexed (Tomudex) Premetrexed (Alimta)
- What type of drug is a purine analogue and give some examples
- Purine analogues are antimetabolites Mercaptopurine (Purinethol) 6-thioguanine (Thioguanine) Fludarabine (Fludara) Cladribine (Leustatin)
- what type of chemotherapy is a pyrimidine analogue?
- Pyrimidine analogues are antimetabolites Fluorouracil (Adrucil) Capecitibine (Xeloda) Cytarabine (Cytosar-U) Gemcitabine (Gemzar)
- what is the dose limiting toxicity for a folic acid chemotherapy?
- myelosuppression, gi and oral ulceration
- what is folic acid's mechanism of action
- Mechanisms of Action Folic acid binds the catalytic domain on dihydrofolate reductase (DHFR) to generate an essential cofactor required for DNA, RNA and protein synthesis. Methotrexate competes with folic acid for the active site of DHFR Premetrexed also inhibits TS.
- what is the clinical indication for some folic acid treatments?
- Methotrexate:Burkitt’s lymphoma, acute lymphoblastic leukemia, trophoblastic choriocarcinoma and metastatic breast, head and neck, ovarian, and cervical carcinomas Ralitrexed: Colon cancer Premetrexed (multi-targeted anti-folate): Mesothelioma, lung cancer in combo with cisplatin
- What are the indications for Pyrimidine antagonists
- Fluorouracil: colon cancer and other solid tumors Capecitabine: breast cancer in combination with taxanes Cytarabine: acute myelogenous leukemia Gemcitabine: pancreatic cancer Clorfarabine: pediatric AML
- What is the dose limiting toxicity for pyrimidine antagonist?
- Myelosuppression, oral and GI ulceration
- what is the mechanism of action for pyrimidine antagonist?
- Inhibition of DNA synthesis by interfering with enzymes involved in pyrimidine synthesis (5-FU: thymidylate synthetase, GEM: ribonucleotide reductase, Cytarabine: DNA polymerase) Cell cycle arrest in G1 phase
- folic acid blocks what in the dna synthesis pathway
- dhfr
- pyrimidine blocks what in dna synthesis
- Thymidylate synthetase
- Purine antagonists are what type of chemotherapy?
- antimetabolites
- what are the purine antagonist indications?
- Mercaptopurine: pediatric acute leukemia Thioguanine: adult acute leukemia in combination with cytarabine Fludarabine: Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia Cladribine: Hairy cell leukemia, CLL, and low grade NHL
- what is the dose limiting toxicity for purine antagonists?
- Myelosuppression
- what is the mechanism of action for purine antagonist?
- Inhibits enzymes involve in the synthesis of nucleotides from purine bases conversion to inhibit DNA and RNA synthesis Fludarabine inhibits DNA polymerase and ribonucleotide reductase
- what are some types of plant alkaloids?
- microtubule disrupters, microtubule stabilizers, Topoisomerase inhibitors, Type 2 inhibitors
- what are some examples of type two inhibitors
- Epipodophyllotoxins Etoposide (VePesid) Teniposide (Vumon)
- what are some examples of topoisomerase inhibitors?
- Topoisomerase inhibitors Type 1 inhibitors Camptothecins Irinotecan (Camptosar) Topotecan (Hycamptin) Type 2 inhibitors
- what are some examples of microtubule stabilizers
- Microtubule stabilizers Taxanes Paclitaxel (Taxol) Docetacel (Taxotere)
- what are some examples of microtubule disrupters
- Microtubule disrupters Vinca Alkaloids Vinblastine (Velban) Vincristine (Vincasar) Vinorelbine (Navelbine)
- what are some of the dose limiting toxcicities of vinca alkaloids?
- Vinblastine: myelosuppression Vincristine: neurotoxicity (bone marrow sparing) Vinorelbine: myelosuppression
- what are some of the indications for vinca alkaloids
- Vincristine - Same activity as vinblastine, less myelotoxicity Vinorelbine – Additional activity against non-small cell lung cancer
- what is the mecanism of action for vinca alkaloids?
- Inhibition of microtubule polymerization, disruption of mitotic spindle and chromosome separation, M phase cell cycle arrest
- Taxanes indications?
- Indications – broad range of solid tumors Paclitaxel – breast, ovarian. Lung, bladder, prostate, gastric, esophageal cancers Docetaxel – semisynthetic derivative with similar activity as paclitaxel
- what is the toxicity of taxanes?
- Toxicity Myelosuppression
- what is the mechanism of action for taxanes?
- Mechanism of action Stabilizes microtubule assembly, inhibition of mitosis and cell division (M phase block)
- what are the indications of campothecins
- Indications (2nd line therapy – used for drug resistant cancers) Irinotecan (CPT11) – Colorectal cancer (5-FU - 1st line therapy; Oxaliplatin - currently 2nd line) Topotecan – Lung and ovarian cancer (taxol or platininum-based therapy - 1st line therapy)
- what is the dose limiting of campothecin?
- Myelosuppression and diarrhea (CPT11)
- what is the mech of action of campothecin?
- Inhibition of topoisomerase I – enzyme that cuts one strand of the DNA to reanneal the cut strand – necessary for unwinding of DNA during replication Campthothecins keep DNA wound into chromosomes so the cell cannot make proteins needed for replication. Cell cycle independent inhibitor SN38 – active metabolite of CPT11
- what are the indications for Epipodophyllotoxins
- Etoposide – testicular, lung, gastric and hematological malignancies Teniposide – acute lymphoplastic leukemia in children
- dose limiting toxicity of Epipodophyllotoxins
- Dose limiting toxicity Nausea, vomiting, myelosuppression, alopecia
- what are the mechanisms of action of Epipodophyllotoxins
- Topoisomerase II inhibition – enzyme that cuts both strands of DNA, passes an unbroken strand of DNA through to reanneal the cut strands.
- what are some Antitumor antibiotics
- Anthracyclines Daunorubicin (Daunamycin and Mitoxantrone (Mutamycin) and Dactinomycin (Actinomycin D) Mitomycin (Mutamycin) Bleomycin (Blenoxane) Mithramycin (Mithracin)
- Anthracyclines indications?
- Doxorubicin and epirubicin – solid tumors Daunamycin and idarubicin – acute leukemias Dose limiting toxicity
- anthracyclines mech of action
- Inhibition of topoisomerase II, DNA intercalation, alteration in membrane fluidity and ion transport, and generation of free radicals Mechanisms of resistance Increased drug efflux by P-gp and MRPs, increased glutathione conjugation, topoisomerase 2 mutations, DNA repair
- mitoxantrone mech of action, clinical indication and does limiting toxicity
- Indications Hormone refractory prostate cancer, non-Hodgkin’s lymphoma, breast cancer, acute myeloid leukemia Dose limiting toxicity Myelosuppression – less cardiotoxic compared to doxorubicin Mechanism of action DNA strand breakage and inhibition of DNA or RNA synthesis
- Bleomycin indications? this drug was in first aid ...
- Squamous cell carcinoma of the cervix, head and neck, skin and vulva Hodkin’s and non-Hodkin’s lymphoma Ovarian and testicular tumors
- bleomycin mech of action
- Mechanism of action Small peptide that binds DNA to cause DNA strand breaks following free radical attack; induces G2 cell cycle arrest
- bleomycin dose limiting toxicity
- Dose limiting toxicity Pulmonary toxicity
- Cytokines: what is an example?
- Interferon-alpha (Intron A)
- what is intro-a's indication
- Indications Hairy cell leukemia, Kaposi sarcoma, squamous cell carcinomas
- what is intron a's mech of action?
- Mechanism of action Stimulate tumoricidal macrophages Direct cytotoxicity to cancer cells
- cytokine: what is another example?
- Interleuken-2 (Proleuken)
- what is interleuken-2 / proleuken's mech of action? and indications?
- Indications Malignant melanoma, squamous cell carcinomas Mechanism of action Increase activity of natural killer cells