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45 Cards in this Set
- Front
- Back
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When does the chromosome replication take place in the cell cycle?
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S Phase
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What are the 3 different classes of chemotherapeutic agents?
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Class 1: Kills all cells regardless of their state of proliferation
Class 2: Cell cycle specific Class 3: Not cell cycle specific, BUT better on proliferating cells |
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What are some of the mechanisms to chemo resistance?
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Transport defects
Somatic mutations Gene Amplification Over-production of membrane glyco-protiens(MDRs) which actively pump drugs out of cells |
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What are the 5 major classes of chemotherapuetic agents?
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Alkylating
Natural (some disrupt the biological process) AntiMetabolites (mimic some natural substrate or cofactor) Enzymes (usually degrade an amino acid) Biological response modifiers (regulatory factors) |
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What are the 5 principle classes of alkylating agents in use?
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Nitrogen Mustards
Ethylenimines Alkylsulfonates Nitrosoureas Triazenes |
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How do the nitrogen mustards work?
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They alkylate DNA at the N-7 position of guanine thus introducing lethal errors in DNA. Alkylated DNA is also subject to DEPURINATION leading to the introduction of both single and double strand breaks.
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What makes Cyclophosphamide so great?
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(Cytoxan)
BC it must be activated by CYP2C9 and hydrolyzed to the active phosphoramide mustard in target cells, hepatotoxicity and other side effects are reduced or eliminated. |
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Which mustard do we want to use for testicular cancer?
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Ifosfamide
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Which ethylenimine is useful for breast and ovarian cancer?
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Thiotepa
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What are nitrosoureas good for?
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(-mustines)
BCNU (carmustine) and CCNU (lomustine) are good for alkylation, DNA crosslinking and carbamoylation of protiens. Since they are lipids they have good penetration into CNS. |
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What are the Nitrogen mustards? (4)
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Melphalan (oral), chlorambucil, cyclophosphamide, ifosfamide
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What makes Streptozocin special?
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It preferentially acts on pancreatic islet cells
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What are the triazenes?
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Dacarbazine- inhibits RNA and protein synthesis more than DNA
Temoxolomide-good for anaplastic astrocytoma |
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What other alkylating agents do we talk about that are not in the 5 principle classes?
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Cisplastin (platinol), Oxalaplatin, Carboplatin and finally Procarbazine
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What is the advantage of Carboplatin over cisplastin?
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Less renal toxicity. Side effects are attenuated by giving amifostine (a free radical scavenger)
Both work by dissociation of chloride ions to leave a positively charged complex which leads to cross linking |
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What are the natural products?
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Vinca alkyloids, Taxanes, Epipodophyllotoxins, Camptothecin derivatives, & Antibiotics
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What are the vinca alkyloids and how do they work?
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Vincristine and Vinblastine.
They bind to tubulin causing depolymerization, thus disrupting microtubule structure. This inhibits spindle fiber formation and mitosis (**M phase of cell cycle) as well as dirupting cytoskeletal movement. |
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What are the toxicities of the Vinca alkyloids?
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NEUROTOXICITY- vincristine
myelosupression, mucositis- vinblastine Vinorelbine is a semisynthetic derivative of vinblastine w increased specificity for microtubules and less neurotoxicity. |
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How does Paclitaxel work?
What is docetaxel? |
Paclitaxel (Taxol) is a diterpine antineoplastic agent from the yew tree.
It inhibits microtubule disassembly, freezing them in the polymerized state. This is in contrast to the vinca alkyloids Docetaxel is a semisynthetic analogue of paclitaxel |
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Which chemo drug inhibits Topoisomerase II and comes from the mandrake?
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(Epipodophyllotoxins)
Etoposide- VP-16 Teniposide- VM-26 *remember* Topoisomerase II is ATP-dependent! |
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What are the camptothecin derivatives and what do they do?
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The campothecin derivitive inhibit Topoisomerase I (NOT ATP-dependent)
Irinotecan Toopotecan These drugs are effective in the treatment of lung and colon cancer (metastatic) |
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What is Dactinomycin?
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AKA Actinomycin D
MODEL INTERCALATING AGENT An antibiotic wich interalates between G:C pairs. |
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What does Dactinomycin do?
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At low levels it inhibits RNA synthesis and at high doses it will inhibit both RNA and DNA synthesis
Side effects are myelosupression and RADIATION SENSITIVITY |
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What are the anthracyclines?
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Daunorubicin (daunomycin)
Doxorubicin (adriamycin) Mitoxantrone |
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What do the anthracyclines do?
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Mechanism is likely: DNA intercalation and introduction of single stranded breaks
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What is the major side effect of anthracyclines?
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A severe side effect of the drug is CARDIOTOXICITY (digitalis unresponsive CHF)
DEXRAZOXANE (Zinecard) is an iro chelator which inhibits free radical formation and can be used to reduce cardiac damage. |
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How does Bleomycin work?
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Bleomycin is a peptide antibiotic which binds to DNA and brings an Fe compex into a position in which oxidation leading to depyrimidation and depurination is facilitated.
Its liek a cross between an intercalating agent and an alkylating agent. |
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Side effects of Bleomycin?
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Because bleomycin is accumulated in the skin, lung and tumor tissue and toxic side effect can be subacute/chronic pneumonitis and skin lesions
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How does Methotrexate (MTX) work?
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MTX is and ANTIMETABOLITE and a folic acid analogue that competitively inhibits the enzyme Dihydrofolate reductase which blocks the conversion of FH2 --> FH4
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What specific rxns does MTX inhibit?
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In the S phase of the cell cycle:
Pyrimidine biosynthesis converting dUMP-->DTMP is inhibited bc FH4 is the methyl DONOR in the rxn 2 purine biosynthesis rxns are also inhibited bc FH4 is a required COFACTOR |
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What are the current strategies of chemotherapy?
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Based on a combination of empiric and theoretical factors:
1) Combinations of drugs 2)Induction and maintenence protocols 3)attempts at cell recruitment 4) attempts at cell syncronization |
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Is MTX bound to plasma proteins?
What are the toxicities of MTX? |
Yes, MTX is bound to plasma proteins
Myelosuppression, renal-, hepato- & neurotoxicity. Leukencephalopathy after intrathecal administration, esp w cranial readiation. |
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What is Leucovorin used for?
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MTX Rescue
It effectively aborts MTX toxicity by supplying reduced folate to cells, thus bypassing the inhibited reductase. It can also potentiate the actions of 5-Flourouracil. |
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What is the principle mechanism for 5-FU?
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5-FU is metabolized to 5-FdUMP which is a potent suicide inhibitor of THYMIDYLATE SYNTHETASE.
defective transcripts are synthesized due to incorporation of 5-FUTP into cellular RNA |
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How can we get additional effectiveness in 5-FU pharmacology?
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Use in presence of allopurinol or AFTER MTX tx.
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What is another flouropyrimidine?
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Capecitabine: this is a 5-FU prodrug whose final step f activation is catalyzed by thymidine phosphorylase, an enzyme which is ELEVATED in metastatic breast and colon cancer.
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What pyrimidine analogue has been found to be effective in tx of hematologic malignancies?
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Cytosine Arabinoside
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What is the mechanism of Cytosine Arabinoside?
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CA is a potent inhibitor of DNA polymerase and when incorporated into DNA causes defective ligation and premature chain termination.
CA is S PHASE SPECIFIC and inhibits DNA synthesis. |
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What is another pyrimidine analogue?
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5-azacytidine
effective in tx of MYELODYSPLASTIC syndrome. |
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What are the prototypic purine analogues?
What is thier mechanism of action? |
6-mercaptopurine & 6-thioguanine
they are converted by hypoxanthine-guanine-phosphoribosyl transferase (HPRT) to nucleoside monophosphates. |
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Describe the metabolism of the purine analogues.
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1)S-methylation by TPMT (6-MP and 6-TG)
(polymorphisms in TPMT may result in variable effectiveness/toxicity) 2) Oxidation by XO to 6-thiouric acid (6-MP only) (XO metabolism is inhibited in the presence of allopurinol) |
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What are the toxicities of the 6-MP and 6-TG?
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myelosupression
hepatotoxicity |
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What other purine analogue is used to tx HAIRY CELL Luekemia?
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Pentostatin
Inhibits adenosine deaminase Neutropenia is dose-limiting toxicity |
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Where does HYDROXYUREA block the cell cycle?
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G1/S boundary
Inhibits ribonucleotide synthesis and DNA synthesis Primary adverse effect is leukopenia |
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What is the prototypic ENZYME for cancer chemotherapy?
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ASPRAGINASE
catalyzes the conversion of asparagine to aspartate. In lymphoid cells, levels of asparagine synthetase are very low, deprivation of asparagine in these cells results in prtein synthesis inhibition |
