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81 Cards in this Set
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Adjuvant therapy definition |
Treatment with chemotherapeutic agent after achieving control of the primary tumor with surgical resection or radiation therapy Use when worried about metastasis, or worried that surgery didn't get everything or there's still microscopic disease (e.g. with osteosarcoma after amputation) |
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Neoadjuvant therapy definition |
Chemo used prior to treatment with other modalities for local tumor control, with the intent of decreasing tumor size E.g. chemo before surgery or radiation Suppresses metastasis, or decreases mass size |
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Induction therapy definition |
Chemo treatment with the intention of a cure First treatment of a cancer, and if this doesn't work, then go to rescue therapy |
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Rescue therapy definition |
Use of chemo after a tumor fails to respond to a previous therapy or after tumor recurrence |
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Palliative chemotherapy definition |
Aims to decrease clinical signs in the case of unresectable or disseminated disease and associated with pain Make the animal more comfortable |
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Therapeutic index |
Ratio between the toxic dose and the therapeutic dose for a drug Very small for chemo in general (high toxicity, and near-toxic levels required for efficacy) |
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Maximal tolerated dose (MTD) |
Highest dose of a drug that can be administered in the absence of unacceptable or irreversible side effects (Chemo is often really close to MTD) |
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Cell cycle nonspecific drugs |
Kill resting cells & dividing cells, act on any part of cell cycle Cyclophosphamide, Chlorambucil, Cisplatin & Carboplatin, Actinomycin D, Adriamycn/doxorubicin, L-asparginase |
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Cell cycle specific drugs |
Kill actively dividing cells |
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Cell cycle specific drugs: S phase |
Methotrexate-5-fluorouracil |
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Cell cycle specific drugs: G2 phase |
Etoposide Bleomycin |
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Cell cycle specific drugs: M phase |
Vincristine Vinblastine Paclitaxel |
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Alkylating agents: subgroups |
Nitrogen mustards Nitrosoureas Traizenes |
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Nitrogen mustard alkylating agents: Drugs |
Mechlorethamine Melphalan Cyclophosphamide Chlorambucil |
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Nitrosoureas alkylating agents: Drugs |
Lomustine (CCNU) Streptozotocin |
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Traizene alkylating agents: Drugs |
Dacarbazine |
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Alkylating agents: General MOA |
Introduce alkyl group that binds covalently into nucleophilic sites on DNA & RNA Can induce interstrand or intrastrand cross-links Can react with 7th position of guanine in each DNA strand -> cross linking & impaired strand separation Alkylation -> misreading of codons, single strand breakage Can bind sites on DNA -> misreading when cell scans for damage -> apoptosis Cell might attempt to repair and excise part of DNA -> misreading Not cell cycle specific |
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Mechlorethamine: Class |
Nitrogen mustard alkylating agent |
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Mechlorethamine: Indication |
Relapsed lymphoma: rescue protocols |
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Mechlorethamine: PK/PD |
IV Extravasation can cause damage |
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Mechlorethamine: Toxicities
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Dose-limiting: GI & bone marrow Major disadvantage: mutagenic & carcinogenic to bone marrow stem cells |
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Mechlorethamine: Problems |
Tech must wear full protection! Strong vesicant Mutagenic & carcinogenic to bone marrow stem cells Damage if extravascular |
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Melphalan: Class |
Nitrogen mustard alkylating agent
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Melphalan: Indication |
Multiple myeloma (combo with prednisone) (Also rescue protocol for lymphoma?) |
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Melphalan: MOA |
DNA cross-linking |
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Melphalan: PK/PD |
PO Actively transported into tumor cells by amino acid transporters (can be blocked by leucine) Can give long-term Does not require activation |
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Melphalan: Toxicities |
Dose limiting: Myelosuppression (check blood a lot for BM function) |
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Cyclophosphamide: Class |
Nitrogen mustard alkylating agent |
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Cyclophosphamide: Indication |
Lymphoma: Part of CHOP protocol Metronomic therapy (low dose over long periods to inhibit angiogenesis) |
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Cyclophosphamide: MOA |
Phosphoramide mustard (most active metabolite) -> bifunctional alkylation & cross-linking |
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Cyclophosphamide: PK/PD |
Inactive -> activated by liver -> degraded by other organs Phosphoramide mustard = most active metabolite PO (repeat over several days) or IV (single larger dose) |
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Cyclophosphamide: Toxicities |
Dose-limiting: Neutropenia & thrombocytopenia Metabolites can cause toxicities -> toxicities might develop after dose is done GI (uncommon) Hemorrhagic cystitis (uncommon): Caused by irritating metabolite acrolein Preventable - give PO, diuresis, give with sodium-2-mercaptoethane sulfonate/Mesna |
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Chlorambucil: Class |
Nitrogen mustard alkylating agent |
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Chlorambucil: Indication |
Chronic lymphocytic lymphoma (CLL) Low-grade GI lymphoma (cats) |
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Chlorambucil: MOA |
Bifunctional alkylation |
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Chlorambucil: PK/PD |
PO (rapid absorption) (No IV version) Activated by liver Passively diffuses into cells (unlike melphalan) |
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Chlorambucil: Toxicities |
Dose-limiting: Neutropenia & thrombocytopenia Lowest toxicity of all alkylating agents -> safe -> used a lot |
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Lomustine (CCNU - cyclohexylchloroethylnitrosourea): Class |
Nitrosoureas alkylating agent |
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Lomustine(CCNU - cyclohexylchloroethylnitrosourea): Indication |
Histiocytic sarcoma (DOC) Lymphoma rescue Epitheliotropic lymphoma Malignancies of the brain Mast cell tumors |
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Lomustine(CCNU - cyclohexylchloroethylnitrosourea): PK/PD |
PO
Wide distribution (incl. CNS & skin, crosses BBB) Extensive hepatic metabolism Highly lipophilic - passively diffuses into cells |
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Lomustine(CCNU - cyclohexylchloroethylnitrosourea): Toxicities |
Dose-limiting: Neutropenia & thrombocytopenia Hepatotoxicity with chronic (3x) administration Extensive hepatic metabolism -> can cause hepatotoxicity (can be dose-limiting, can be fatal!) --prophylactic liver protectants Long NADIR: ~3w in dogs, up to 6w in cats Cats are really sensitive, not often used in cats unless other things fail? |
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Streptozotocin: Class |
Nitrosoureas alkylating agent |
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Streptozotocin: Indications |
Insulinoma only (Very effective for insulinoma) |
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Streptozotocin: PK/PD |
Uptake intoβ-cells by GLUT 2
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Streptozotocin: Toxicities |
Dose-limiting: Diabetes (but diabetes is better than cancer...) Severe renal toxicity (Almost no BM toxicity) Severe toxicities, but effective drug |
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Dacarbazine (DTIC): Class |
Traizene alkylating agent |
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Dacarbazine (DTIC): Indication |
Lymphoma rescue Melanoma Brain malignancies |
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Dacarbazine (DTIC): MOA |
Methylation in 3-methyl adenine, 7-methyl guanine, & O-6-methyl guanine |
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Dacarbazine (DTIC): PK/PD |
IV over several hours (Poor oral absorption - not PO) Prodrug -> activated by P450 (liver, lungs) Heavily metabolized in liver Excretion: urine Crosses BBB |
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Dacarbazine (DTIC): Toxicities |
Dose-limiting: GI Neutropenia & thrombocytopenia |
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Alkylating agents: Resistance mechanisms |
Decreased drug influx Increased production of nucleophilic substance (glutathione) that competes for binding target Increased DNA repair mechanism Increased metabolic inactivation of drug (Not affected by Pgp!) No cross-resistance (if one drug stops working, can try another in same group) |
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Platinum agents: Drugs |
Carboplatin Cisplatin |
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Carboplatin: Class |
Platinum agent |
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Carboplatin: Indication |
Osteosarcoma Anal sac adenocarcinoma Transitional cell carcinoma |
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Carboplatin: MOA |
Covalently bind DNA interstrands (90%) & intrastrands (10%) -> alkylates and changes overall DNA shape |
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Carboplatin: PK/PD |
Metabolized by reaction with H2O & binding to plasma proteins Excretion: Urine (70% unchanged) |
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Carboplatin: Toxicities |
Dose-limiting: BM suppression @ 7d. and/or 21d. Long biphasic NADIR Decreased renal function/GFR -> carboplatin stays in body longer -> increased toxicity (No nephrotoxicity) |
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Cisplatin: Class
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Platinum agent |
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Cisplatin: Indication |
Osteosarcoma |
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Cisplatin: PK/PD |
Excretion: Renal (50% unchanged) |
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Cisplatin: Toxicities |
Severe nephrotoxicity!!! (Immense diuresis several hours before/after dose) Cisplatin gives longer survival than carboplatin (1-2mo. longer) - not really worth it with such increased toxicity |
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Platinum agents: Resistance |
No cross-resistance |
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Platinum agents: General MOA |
Alkylation (sometimes called "non-traditional alkylating agents) Not cell cycle specific |
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Antitumor antibiotics: Drugs |
Doxorubicin (Adriamycin) Mitoxantrone Actinomycin D |
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Doxorubicin: Class |
Antitumor antibiotic |
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Doxorubicin: Indication |
Almost every cancer |
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Doxorubicin: MOA |
DNA intercalation Inhibit DNA & RNA polymerase Inhibit topoisomerase -> blocks DNA repair DNA alkylation Induce oxygen reactive species Inhibit thioredoxin reductase Very effective - messes up DNA and prevents repair |
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Doxorubicin: PK/PD |
IV over 20min. (not all at once, to reduce GI & cardio toxicities) Elimination: Liver (mostly), kidneys Smaller dogs/cats: Dose by mg/kg, not BSA (because so toxic) |
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Doxorubicin: Toxicities |
Dose-limiting: Hypersensitivity/anaphylaxis (diphenhydramine) BM suppression GI toxicity (metronidazole, cerenia...) Dose-related cardiotoxicity (decreased contractility) - cumulative/lifetime dose Cats: Limiting toxicity is nephrotoxicity/tubular damage! (Not heart) Extravasation -> really really bad, extremely bad, can be lethal Prescreen dogs for heart problems, especially predisposed breeds More effective than synthetic versions, but more toxic |
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Dexrazoxane (Zinecard) |
Potent intracellular chelating agent - chelates iron & decreases free radicals Can use for doxorubicin, to protect against cardiotoxicity & extravasation necrosis/sloughing |
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Mitoxantrone: Class |
Antitumor antibiotic Synthetic analog of doxorubicin |
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Mitoxantrone: Indication |
Transitional cell carcinoma (better than doxorubicin for some reason)
Lymphoma rescue (not as good as doxo) Carcinomas |
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Mitoxantrone: MOA |
DNA intercalation Inhibit DNA & RNA polymerase Inhibit topoisomerase II DNA alkylation (No oxygen reactive species like doxorubicin) |
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Mitoxantrone: PK/PD |
Elimination: Urine & feces, ~30% unchanged |
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Mitoxantrone: Toxicities |
Dose-limiting: GI Myelosuppression |
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Actinomycin D: Class |
Antitumor antibiotic Synthetic copy of doxorubicin |
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Actinomycin D: Indications |
Lymphoma only |
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Actinomycin D: MOA |
Interacts with single & double stranded DNA |
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Actinomycin D: PK/PD |
IV Elimination: Urine (20% unchanged) & feces (15% unchanged) Passive diffusion into cells |
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Actinomycin D: Toxicities |
Dose-limiting: GI Myelosuppression Extravasation is bad (not as bad as doxorubicin but still bad) (Not cardiotoxic) |
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Antitumor antibiotics: Resistance mechanisms |
Increased efflux (mdr1/Pgp) Increased antioxidant enzymes (GST, SOD) Increased DNA repair Increased drug conjugation (GST) |
