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PMCOL 344 Midterm 2 Exam Latest Update
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PMCOL 344 Midterm 2 ExamLatest Update
Mechlorethamine - Answer Nitrogen mustard alkylating agent: S-phase specific, bind
covalently to DNA, mutagenic (given in single high dose)
-Hodgkin's lymphoma
-Dose-limiting: myelosuppression
Chlorambucil - Answer Nitrogen mustard alkylating agent: S-phase specific, bind
covalently to DNA, mutagenic (given in single high dose)
-Chronic lymphocytic leukemia
-Dose-limiting: myelosuppression
Malphalan - Answer Nitrogen mustard alkylating agent: S-phase specific, bind
covalently to DNA, mutagenic (given in single high dose)
-Multiple myeloma (in combination with prednisone)
-Dose-limiting: myelosuppression
Cyclophosphamide (CPX) - Answer Nitrogen mustard alkylating agent: S-phase specific,
bind covalently to DNA, mutagenic (given in single high dose)
-Dose-limiting: myelosuppression, hemorrhagic cystitis
-Activated by hepatic cytochrome oxidase, then non-enzymatic conversion to acrolein
and phosphoramide mustard (active)
-Given with Mesna
Acrolein - Answer Side product of activation of CPX and ifosfamide
Potent lung irritant, also hemorrhagic cystitis and hematuria
-Giving Mesna with ifosfamide/CPX treatment forms adduct with acrolein to detoxify it,
allows higher doses of drug
Mesna - Answer Forms adduct with acrolein to detoxify it, allows higher doses of drug
Always given with ifosfamide
- Answer
,Ifosfamide - Answer Nitrogen mustard alkylating agent: S-phase specific, bind
covalently to DNA, mutagenic (given in single high dose)
-Dose-limiting: myelosuppression, hemorrhagic cystitis
-Lymphoid and myeloid malignancies
-Always given with Mesna
Carmustine (BCNU) - Answer Nitrosourea alkylating agent: requires activation in the
liver to active intermediate
-Lipid soluble: can get into cell through diffusion and act without the cell being active,
also can cross BBB so useful in brain tumours
-Myelosuppression, leukemogenic (causes leukemia), hepatotoxicity
Bifunctional agent
Lomustine (CCNU) - Answer Nitrosourea alkylating agent: requires activation in the liver
to active intermediate
-Lipid soluble: can get into cell through diffusion and act without the cell being active,
also can cross BBB so useful in brain tumours
-Myelosuppression, leukemogenic (causes leukemia), hepatotoxicity
Monofunctional agent, only one reactive side chain
Busulfan - Answer Alkyl sulphonate, alkylating agent.
Bifunctional, creates G-G and A-G intrastrand crosslinks
-Depression of blood cells, used in bone marrow transplant regimes to wipe everything
out (in chronic myelogenous leukemia)
Temozolomide - Answer Triazine alkylating agent, prodrug of dacarbazine
Interact with guanine N7 or O6
Used for glioblastomas and melanomas
Dacarbazine - Answer Triazine alkylating agent
Interact with guanine N7 or O6
Used for glioblastomas and melanomas
Thiotepa - Answer Ethylenimine alkylating agent
Lymphoma, breast, ovary, bladder, also used for malignant effusions
, Alkylating agent resistance - Answer -Decreased transport
-Increased intracellular thiol concentration, glutathione detoxifies drugs (depleting
glutathione helps increase effect of alkylating agents
-Increased glutathione S-transferase which detoxifies reactive intermediates (step
before alkylation)
-Enhanced DNA repair
MGMT - Answer DNA repair enzyme
Methylation of promoter leads to less MGMT, less DNA repair, more responsive to
alkylating agents
Methylation of promoter in gliomas is predictor of responsiveness to triazines
Cisplatin - Answer DNA-reactive, bifunction and forms intrastrand cross links (mostly
G-G, can be A)
-Uptake: diffusion or through copper transporters
-Once inside the cell, low Cl- causes Cl- to leave leading to hydrolysis and activation
-Cell cycle non specific
Used in testicular (PEB), ovarian cancer, solid tumours
Renal toxicity through generation of ROS, nausea and vomiting (give with antiemetic
adjuvant therapy)
-Resistance through downregulation of copper transporter, increased efflux, increased
DNA repair, increased thiols (GSH forms complex with and inactivates active cisplatin)
- Answer
Methotrexate (MTX) - Answer Similar structure to folic acid but has amino and methyl
groups that allow binding to dihydrofolate reductase but blocks activity
Free version inhibits DHFR, polyglutamated form inhibits DHFR and TYMS
Used in breast cancer, childhood acute lymphoblastic leukemia
-High dose used in osteogenic sarcoma with leucovorin rescue
Ulceration, myelosuppression, pulmonary infiltrates and fibrosis
-Resistance by reduced uptake, increased efflux by ABC's, altered target enzymes,
reduced polyglutamation, increased thymidine uptake (salvage pathway)
Leucovorin - Answer Rescues normal tissue from MTX toxicity: enters via folate
transporters, then enters folate cycle after DHFR to circumvent MTX block
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