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172 Cards in this Set
- Front
- Back
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Adjuvant Therapy |
Treatment with chemotherapeutic agent after achieving control of the primary tumor with surgical resection or radiation therapy |
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Neoadjuvant Therapy |
Chemotherapy used prior to treatment with other modalities for local tumor control, with the intent of decreasing tumor size |
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Induction Therapy |
Chemotherapy treatment with the intention of a cure |
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Rescue Therapy |
Use of a chemotherapy after a tumor fails to respond to a previous therapy or after tumor recurrence |
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Palliative Chemotherapy |
Aims to decrease clinical signs in the case of unresectable to disseminated disease & associated with pain |
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Therapeutic Index |
The ration between the toxic dose and the therapeutic dose for that drug |
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Maximal Tolerated Dose (MTD) |
The highest dose of a drug that can be administered in the absence of unacceptable or irreversible side effects |
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Therapeutic Modalities in Oncology |
Surgery Radiation Chemotherapy Immunotherapy Targeted therapy |
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The majority of cells in healthy tissue are in which phase of the cell cycle? |
G0 |
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Once the cell cycle crosses the __________, the cell cycle becomes self-directed |
Restriction point G0 --> G1 |
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CDK activity requires _______________ to be activated |
Cyclins Different cyclins for different parts of the cell cycle |
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Which drugs are cell cycle non-specific? What does that mean? |
Kills resting cells & dividing cells Cyclophosphamide Chlorambucil Cisplatin, carboplatin Actinomycin D Adriamycin L-asparginase |
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Which drugs are cycle specific? What does that mean? |
Kills actively diving cells S1 - Methotrexate - Fluorouacil G2 - Etoposide - Bleomycin M - Vincristine - Vinblastine - Paclitaxel |
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Limit of Detection Amount |
Approximately 10^9 cells |
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Each chemotherapy course gives _________ kill, but _______ regrowth occurs between courses |
Each chemotherapy course gives 2 log kills, but 1 log regrowth occurs between courses (There is a limit to how often you can give chemotherapy drugs, neoplasm grows during the time between treatments) |
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Chemotherapy agents are dosed based on __________ |
Body surface area (mg/m2) Small dogs & cats (under 15kg) may be calculated differently (body weight mg/kg) |
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Rescue Therapy |
Therapy given after failure to respond to standard therapy |
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What are the 2 primary mechanisms of chemotherapy drug resistance? |
Cellular mechanisms Anatomical resistance |
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Methods of Anatomical Resistance |
Tumor hypoxia (physical distance from blood vessels, imperfection of malignant blood vessels) Physiological barriers (limited penetration to certain locations - BBB, skin, bone marrow...) |
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Cellular Mechanisms of Resistance |
Alteration of drug targets Multi-drug resistance Enhanced survival |
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How does multi-drug resistance occur? |
Drug efflux pump (Pgp) Drug conjugation with glutathione |
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How does enhanced survival occur (as a method of resistance)? |
Evasion of apoptosis Increased DNA repair |
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How does alteration of drug targets occur (as a method of resistance)? |
Up regulation of targeted proteins Mutation of target binding site |
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Why is an area of necrosis within a tumor a bad sign? |
It is growing FAST. The body can't keep up with creating vasculature to supply the tumor. |
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Chemotherapy agents should be mixed in a __________ |
Fume hood (Class IIB) Remember: Chemotherapy can cause cancer! (DNA mutations) |
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Does chemotherapy require special IV sets? |
Yup, closed sets |
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Chemotherapy Protection Gear |
Chemotherapy gloves (or double up regular gloves) Face mask Eye protection +/- face shield Chemo gown |
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Major Categories of Alkylating Agents |
Nitrogen Mustards Nitrosoureas Traizenes |
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Nitrogen Mustard Drugs |
Mechlorethamine (Mustargen) Cyclophosphamide (Cytoxan) Chlorambucil (Leukeran) Melphalan (Alkeran) Ifosfamide |
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Nitrosourea Drugs |
Lomustine (CCNU) Streptozocin |
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Traizene Drugs |
Dacarbazine |
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Alkylating Agent MOA |
Introduces an alkyl group that binds covalently into nucleophilic sites on DNA & RNA Induces monofuctional or bifunctional adducts that generate cross-links Results in misreading of codons & single strand breakage --> induces apoptosis if severe enough |
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Alkylating agents mostly react with the __________ in each strand of DNA |
7th position of guanine |
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Mechlorethamine Category? Method of administration? What is it used for? |
Alkylating agent (nitrogen mustard) Given IV Used in rescue protocols for relapsed lymphoma |
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Mechlorethamine Major Disadvantage |
Mutagenic & carcinogenic to bone marrow & stem cells Need SUPER protective gear! |
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Do alkylating agents have issues with cross resistance? |
NO! If one doesn't work, try another |
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Mechlorethamine |
GI and bone marrow toxicities (dose-limiting toxicities) |
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Melphalan MOA |
DNA cross-linking |
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How does melphalan enter into tumor cells? |
Actively transported into tumor cells by amino acid transporters |
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Melphalan Toxicity |
Myelopsuppression |
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Melphalan Clinical Used |
Multiple myeloma (in conjunction with prednisone) |
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Cyclophophamide MOA |
Metabolized in the liver to an active metabolite - phosphoramide mustard |
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Cyclophophamide Administration |
PO or IV To achieve proper concentration levels, oral dosing must be given over a course of a few days (to avoid toxicity) |
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Cyclophophamide Limiting Toxicity |
Neutropenia & thrombocytopenia Hemorrhagic cyctitis is uncommon and can be prevented with administration of mercaptoethane sulfonate (mesna) or fluid therapy |
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What is mesna (mercaptoethane sulfonate)? |
A drug given along with cyclophophamide to prevent hemorrhagic cyctitis |
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CHOP protocol |
Week 1: Vincristine Week 2: Cyclophosphamide Week 3: Vincristine Week 4: Adryamicin Week 5: No treatment + prednisoee for the first month |
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CHOP protocol is used to treat_________ |
Lymphoma Also used for metronomic therapy |
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Metronomic Therapy |
The use of very low dosing of cyclophosphamide for prolonged periods to inhibit angiogenesis in solid tumors CHOP protocol, toceranib |
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How does chlorambucil enter the tumor cells? |
Passive diffusion |
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Chlorambucil MOA |
Activated by the liver Caused bifunctional alkylation |
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Chlorambucil Administration |
PO (rapidly absorbed) |
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Chlorambucil limiting toxicity |
Neutropenia & thrombocytopenia Has the lowest toxicity of all alkylating agents |
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Which alkylating agent has the lowest toxicity? |
Chlorabucil |
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Chlorambucil Clinical Use |
Chronic lymphocytic leukemia Low-grade GI lymphoma |
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Lomustine Classification |
Alkylating agent (nitrosourea) |
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Lomustine Administration |
PO |
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How does lomustine enter tumor cells? |
Passive diffusion (highly lipophilic) |
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Lomustine MOA |
Alkylation leading to DNADNA and DNA-protein cross-links |
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Lomustine Metabolism |
Extensive hepatic metabolism |
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Lomustine Distribution |
Extensive, including BBB & skin |
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Lomustine Limiting Toxicity |
Neutropenia & thrombocytopenia Chronic administration (3 times) can result in liver toxicity Cats are especially susceptible |
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Lomustine Clinical Use |
Histiocytic sarcoma Lymphoma rescue Epitherliotropic lymphoma Malignancies of the brain Mast cell tumor |
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DOC for Hitiocytic Sarcoma |
Lomustine |
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How long can you give lomustine without side effects? |
Dogs - 3 weeks Cats - 6 weeks |
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How does streptozotocin enter into tumor cells? |
Cellular uptake into beta cells by GLUT 2 |
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Streptozotocin Limiting Toxicity |
Severe renal toxicity (induce diuresis!!!) Induction of diabetes |
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Stretozotocin Clinical Use |
Insulinoma |
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Dacarbazine Administration |
IV over several hours |
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Dacarbazine MOA |
Prodrug that is activated by p450 (lungs, liver) Induced methylation |
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Which alkylating agents can cross the BBB? |
Lomustine Dacarbazine |
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Daarbazine Metabolism & elimination |
Heavily metabolized in the liver Excreted in the urine |
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Dacarbazine Limiting Toxicity |
GI Issues Neutropenia & thrombocytopenia |
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Dacarbazin Clinical Use |
Lymphoma rescue Melanoma Brain malignancies |
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Alkylating Agent Resistance Mechanisms |
- Decrease of drug influx - Increased production of neucleophilic substance (glutathione) that competes for the target - Increased DNA repair mechanism - Increased metabolic inactivation of the drug NO effect by Pgp! |
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Carboplatin MOA |
Covalently binds DNA |
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Carboplatin Metabolism |
Metabolized by reaction with H2O and binding to plasma proteins |
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Carboplatin Elimination |
Excreted in urine 70% unchanged |
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Carboplatin has a strong correlation with _________ |
renal function (renal malfunction can result in increased toxicity) |
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Carboplatin Limiting Toxicity |
Bone marrow suppression Cisplatin can cause nephrotoxicity, but carboplatin does not |
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Carboplatin Clinical Use |
Osteosarcoma Anal sac adenocarcinoma Transitional cell carcinoma |
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Platinum Agents |
Carboplatin Cisplatin |
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Never use cisplatin in ))))))) |
Cats! Severe renal toxicity (even with dogs you need extreme diuresis) |
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Cisplatin Excretion |
Renal excretion, 50% unchanged |
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Cisplatin Clinical Used |
Osteosarcoma |
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Antitumor Antibiotics |
Doxorubicin Mitoxantrone Actinomycine D Microbial fermentation byproducts: anthracyclines, mitomycins, & actinomycins |
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Synthetic forms of antitumor antibiotics were made to _____________ |
reduce toxicity |
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Doxorubicin Administration |
IV over 20 minutes (for toxicity reasons) |
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Doxorubicin MOA |
DNA intercalation (deforms the shape) Inhibits DNA & RNA polymerase and topoisomerase II DNA alkylation Induction of oxygen reactive species Inhibition of thioredoxin reductase Damages DNA in LOTS of ways & prevents repair |
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Doxorubicin Limiting Toxicities |
Hypersensitivity Bone marrow suppression GI toxicity Cardiotoxicity (cumulative!) Nephrotoxic in cats (primary limiting factor) |
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Cardiotoxicity Effects of Doxorubicin
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Reduction of contractility Cumulative! Required a cardiology screening after a certain amount |
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Doxorubicin Elimination |
Liver (mostly) & kidneys |
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How would you dose doxorubicin in smaller dogs & cats? |
mg/kg (rather than body surface area) |
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Doxorubicin Clinical Use |
Almost every type of cancer |
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Doxorubricin Side Effects |
Free radicals Severe tissue damage with extravasation, heart damage Do NOT use a vein that has recently been used for anything |
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Dexrazone-Zinecard |
Intracellular chelating agent - reduces the amount of free radicals Reduces the chances for heart damage & tissue damage from extravasation |
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What can be given to help treat tissue damage associated with doxorunicin extravasation? |
Dexrazoxane-Zinecard Give 10x the extravasated dose in a limb other than the affected limb Give for up to 3 days, extravasation effects can occur days to weeks later, if you suspect it, treat immediately |
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Which drugs are antitumor antibiotics? |
Mitoxantrone Actinomycin D |
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_______ is a synthetic analog of doxorubicin |
Mitoxantrone |
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Mitoxantrone MOA |
DNA intercalation & alkylation Inhibits DNA & RNA polymerase, topoisomerase 2 |
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What are the benefits of mitoxantrone vs. doxorubicin? |
Does not induce reactive oxygen species But generally considered less effective |
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Mitoxantrone Clinical Use |
Transitional cell carcinoma Lymphoma rescue Carcinomas |
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Mitoxantrone Dose Limiting Toxicity |
GI issues Myelosuppression |
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Actinomycin D Administration |
IV |
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Actinomycin D MOA |
Absorbed into cells by passive diffusion Interacts with single & double strand DNA |
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Actinomycin D Clinical Use |
Lymphoma |
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What drugs can cause tissue damage with extrasavation? |
Doxorubricin Actinomycin D Vincristine & Vinblastine |
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Actinomycin D Dose Limiting Toxicity |
GI issues Myelosuppresion Extravasation tissue damage |
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Antitumor Antibiotic-Drug Resistance Mechanisms |
Increased efflux via MDR1 Increased antioxidant enzymes Increased DNA repair Increased drug conjugation This is why a combination of drugs is used - to overcome resistance mechanisms |
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Antimetabolies What are they? MOA? How do they enter the cells? |
Similar structure to metabolites, but can't be used by the cell Interferes with production of nucleic acids, RNA, & DNA Enters cells via a specific active transporter |
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When do antimetabolites have a predominate effect? |
S phase |
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Antimetabolite Groups |
Folate antagonists Purine analogs Pyrimidine analogs |
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Antimetabolie Drugs |
Cytosine arabinoside (Cytatabine) 5-Flurorouracil Gemcitabine |
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Cytosine arabinoside is a analog of ________ |
Deoxycytidine |
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Cytosine Arabinoside MOA |
Antimetabolite DNA polymerase alpha inhibitor following phosphorylation Is incorporated into DNA |
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Cytosine Arabinoside Administration |
IV or SQ |
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Which antimetabolite can cross the BBB? |
Cytosine arabinoside |
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Which antimetabolite needs to be given as a CRI? |
Cytosine arabinoside Has a very short T1/2 - the longer it is infused, the better therapeutic effect (& higher toxicity) |
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Cytosine Arabinoside Dose Limiting Toxicity |
Myleosupression GI upset (not common) |
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Cytosine Arabinoside Clinical Use |
Lymphoma Leukemia Meningioencephalitis |
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5-Fluorouracil is an analog of _____ |
Uracil |
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5-Fluorouracil MOA |
Antimetabolite Activation of the drug causes thymidine and deoxy-urinine depletion - interferes with DNA & RNA synthesis & integrity |
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5-Fluorouracil Administration |
IV |
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5-Fluorouracil Metabolism |
Liver Topical cream (not much in vet med) |
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NEVER give ___________ to cats! |
5-Fluorouracil Cisplatin |
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5-Fluorouracil Dose Limiting Toxicity |
Myelosupression GI upset |
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5-Fluorouracil Clinical Use |
Carcinomas |
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Gemcitabine MOA |
Antimetabolite Inhibits DNA polymerase Depletion of deoxyribonucleotide pools Active molecule is incorporated into DNA leading to strand termination |
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Gemcitabine Administration |
IV Longer infusion increases cellular uptake |
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Gemcitabine Dose Limiting Toxicity |
Myelosupression
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Gemcitabine Clinical Use |
Carcinomas |
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Antimicrotubule Agents Types? MOA? |
Taxens & vinca alkaloids Interferes with polymerazation or depolymerization of the mictotubules (M phase) |
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Antimictotubule Drugs |
Vincristine
Vinblastine |
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Vincristine & Vinblastine MOA |
Antimicrotubule drug - disrupts the mitotic spindle |
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Vincristine & Vinblastine Administration |
IV |
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Vincristine & Vinblastine Metabolism |
Liver |
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Vincristine & Vinblastine Dose Limiting Toxicity |
GI upset, including the ileus Peripheral neurotoxicity |
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Vincristine Clinical Use |
Lymphoma (CHOP protocol) Immune mediated thrombocytopenia |
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Vinblastine Clinical Use |
Mast Cell Tumor |
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Vincristine & Vinblastine Drug Resistance |
MDR1 up regulation Mutation of the microtubule target |
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L-Asparaginase MOA |
Hydrolysis of L-asparagine to L-aspartic acid - less L-asparagine available disrupts protein synthesis Malignant lymphoblasts cannot produce their own L-asparagine! |
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L-Asparaginase Administration |
IV or SQ |
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L-Asparaginase Dose Limiting Toxicity |
Hypersensitivity - can prevent with antihistamine & dexamethasone |
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L-Asparaginase Clinical Use |
Lymphoma rescue |
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Tyrosine Kinase Inhibitors Drugs |
Imatinib (Gleevec) Toceranib (Palladia) Masitinib (Kinavet) |
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Imatinib MOA |
Tyrosine kinase inhibitor Binds to ATP to prevent phosphorylation of the BCR-ABL tyrosine kinase which is chronically expressed in chronic myeloid leukemia |
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The Philadelphia chromosome of chronic myeloid leukemia expresses ________ which is targeted by ______________ |
BRC-ABL tyrosine kinase Imatinib (tyrosine kinase inhibitor) |
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Masitinib Clinical Use |
Canine mast cell tumors (FDA approved) |
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Toceranib Administration |
Oral - 3 times a week |
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Toceranib & Masitinib Dose Limiting Toxicity |
GI upset Myelosupression Proteinuria |
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Toceranib Resistance |
Second mutation at the target site
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What drugs target the C-kit mutation? |
Toceranib Masitinib Both tyrosine kinase inhibitors |
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Vaccine immunotherapy exists for which cancer? |
Melanoma - xenogenic DNA vaccine |
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Melanoma Vaccine MOA |
Xenogenic DNA vaccine Targets a gene in human tyrosinase which is a glycoprotien essential for melanin synthesis - inserted into a plasmid |
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The melanoma is commonly combined with what other treatment method? |
Surgery The vaccine is NOT very effective! But is sometimes used when there is no other option. |
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Mast Cell Tumor Treatments |
Lomustine Vinblastine Toceranib Masitinib |
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Carcinoma Treatments |
Carboplatin (transitional cell & anal sac) Mitoxantrone (transitional cell + others) 5-Fluorouracil Gemcitabine |
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Multiple Myeloma Treatments |
Melphalan (in conjunction with prednisone) |
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Leukemia Treatment |
Chlorambucil (chronic lymphocytic) Cytosine Arabinoside Imatinib (chronic myeloid) |
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Can you give L-Asparaginase with low lymphocyte counts? |
Yes! It only targets lymphoblasts |
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Rescue Treatments for Lymphoma |
Mechlorethamine Lomustine Dacarbazin Mitoxantrone L-Asparaginase |
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Primary Lymphoma Treatments |
CHOP protocol Chlorambucil (low grade GI lymphomas) Lomustine (epitherliotropic) Actinomycin D Cytosine arabinoside |
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Are most chemotherapy drugs FDA approved for use in veterinary species? |
NO! Used off-label for palliative care Drugs that are veterinary approved: Tyrosine kinase inhibitors Canine melanoma vaccine |
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Melanoma Treatments |
Dacarbazin Canine melanoma vaccine |
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Histiocytic Sarcoma Treatment |
Lomustine |
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Toceranib MOA |
Blocks a mutation at exon 11 which constantly activates the C-kit receptors |
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Toceranib is essentially a veterinary version of ______ |
Imatinib (Gleevec) |
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Brain Malignancy Treatments |
Lomustine Dacarbazine |
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Toceranib Targets |
C-kit mutation Also factors involved in angiogenesis: PDGFR VEGFR-11 |
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Osteosarcoma Treatment |
Cisplatin Carboplatin |
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Toceranib Clinical USe |
Mast cell tumor GI stromal tumor Metronomic therapy |
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When would you choose mastinib over toceranib? |
If its cheaper (they are essentially the same) |
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Melanoma Vaccine Administration |
Via pneumonic device |
