Chemo drugs Flashcards
(23 cards)
Mustargen (Mechlorethamine)
- Nitrogen mustard = form reactive intermediates that attack neutrophilic sites in DNA
- Undergoes spontaneous hydrolysis and neutrophilic reactive centers capable of forming DNA cross-links
- Spontaneous degraded
- DLT = GI and bone marrow
Strong vesicant* = sodium thiosulfate administration through catheter/directly into site (same amount as drug)
Melphalan
- Nitrogen mustard = form reactive intermediates that attack neutrophilic sites in DNA
- DIRECT alkylating activity
- Active transport into cells via AA transporters (blocked by leucine)
- 20-35% unchanged urine
- DTL = myelosuppression (neut/thromb)
Dosing = 0.1mg/kg daily 10-14 days then 0.05mg/kg daily
OR, 7mg/m2 daily x 5 days every 3 wks
Cyclophosphamide
- Nitrogen mustard = form reactive intermediates that attack neutrophilic sites in DNA
- PRODRUG activated by microsomal mixed function oxidases (CYP450) in liver via ring oxidation to 4-OHCP > spontaneous and reversible ring opening to amino aldehyde aldophosphamide = irreversible breakdown to phosphoramide mustard (active metabolite) and acrolein
- Phosphoramide mustard capable of bifunctional alkylation and cross-linking
- DLT = neutropenia – SHC secondary to acrolein
- SHC treatment = NSAIDs, oxybutynin
Dosing = 200-250mg/m2 PO
- fractionated schedule = 50-75mg/m2 PO for 3-4 consecutive days
- metronomic = 12.5mg/m2/day
Ifosfamide
- Nitrogen mustard = form reactive intermediates that attack neutrophilic sites in DNA
- PRODRUG activated by microsomal mixed function oxidases (CYP450) and metabolite capable of bifunctional alkylation
- DLT = myelosuppression, neurotoxic, nephrotoxic, damage to bladder epithelium
Sarcomas/FISS
Dosing = 375mg/m2 IV in dogs and 900mg/m2 IV in cats - given slow with saline diuresis every 3 weeks
Chlorambucil
- Nitrogen mustard = form reactive intermediates that attack neutrophilic sites in DNA
- Nitrogen mustard derivative that enters cells via passive diffusion = direct bifunctional alkylating ability
- Extensive hepatic metabolism
- Active metabolite = phenylacetic acid
- DLT = myelosuppression (granulocytopenia and thrombocytopenia)
Dosing
Dogs = 3-6mg/m2 SID (4mg/m2 daily tolerated long term)
Cats = 2mg/cat EOD or MWF, OR 20mg/m2 every 2 weeks
CCNU
- Nitrosourea agent
- Highly lipid soluble and enters cells via passive diffusion (cross BBB)
- At physiologic pH will spontaneously decompose to a reactive center capable of DNA alyklation and DNA-DNA and DNA-protein cross-links
- Extensive hepatic metabolism (phenobarbital increases clearance)
- DLT = myelosuppression (acute neutropenia with irreversible thrombocytopenia possible), delayed nadir in cats, ALT elevations in dogs
Dosing
Dogs = 70-90mg/m2 PO q3wks
Cats = 40-60mg/m2 PO or 10mg/cat q4-6wks
Streptozotocin
- Nitrosourea agent - naturally occurring
- DNA alkylation and inhibition of DNA synthesis
- Cellular uptake dependent on GLUT2 transporter
- DLT = nephrotoxicity (Fanconi and DI), diabetes
Dosing = 500mg/m2 IV q2wks with saline diuresis
Dacarbazine (DTIC)
- Methylating agent = methylates nucleic acids
- MGMT will repair damage and cause resistance
- PRODRUG activated by hepatic CYP450 =
5-aminoimidazole carboxamide and methyldiazonium ion (active methylating intermediate) = 3 DNA methylation products that are responsible for cytotoxicity- 3-methyl adenine
- 7-methyl guanine
- O6-methyl guanine
- liver metabolism and urine excretion
- DLT = GI toxicity and occasional myelosuppression
Dosing
single agent = 800-1000mg/m2 q3wks
combo (dox or CCNU) = 600-800mg/m2, or 200mg/m2/day x 5 days
*NOT used in Cats
Procarbazine
- Methylating agent
- MGMT will repair damage and cause resistance
- PRODRUG requires chemical/metabolic activation CYP450 = inhibition of DNA and RNA synthesis with DNA methylation to form O6-methyl guanine
- rapidly absorbed with equilibration within blood and CSF
- renal excretion
- DLT = GI and rarely myelosuppression
Dosing = 50mg/m2/day PO x 14 days
Temozolomide
- Methylating agent = methylates nucleic acids
- Radiosensitizer
- 7-methyl guanine and O6-methyl guanine
- MGMT will repair damage and cause resistance
Dosing = 150mg/m2 PO for 5 days q3wks
Doxorubicin
- Anthracycline
- Antitumor antibiotic
- Multimodal mechanism of cellular toxicity
- DNA intercalation
- Inhibition of RNA and DNA polymerases,
topoisomerase II
- Alkylation of DNA
- Generate ROS
- Perturbation of cellular calcium homeostasis
- Inhibition of thioredoxin reductase
- Interaction with plasma membrane components - Extensive distribution into tissues and binds to cellular DNA and anionic lipids
- Elimination through renal and biliary of parent drug and metabolism to doxorubicinol (via side chain reduction mediated by aldo-keto reductases) and 7-hydroxy aglycone (via reductive cleavage of sugar moiety by liver and extrahepatic tissues)
- Radiosensitizer
- rapid admin = anaphylactoid reactions
- DLT = myelosuppression, GI toxicity, acute cardiotoxicity, and cumulative cardiac toxicity
Cats = cumulative nephrotoxicity
Dosing:
- Dogs = 30mg/m2 IV q2-3wks (15-30min)
(cumulative dose = 150-240mg/m2)
- Cats or dogs <15kg = 25mg/m2 or 1mg/kg IV
*Vesicant = cold compress and Dexrazoxane (10x dox dose) IV (in different vein from site of extravasation), immediately, 24hr-post and 48hr-post
Mitoxantrone
- Anthracendione
- synthetic doxorubicin analog = similar activity for DNA intercalation and inhibition of RNA and DNA polymerases and topoisomerase II (no oxidative damage and reduced ROS generation)
- Not extensively metabolized
- <30% excreted unchanged in urine and feces
DLT = myelosuppression
Dosing
- Dogs = 5-5.5mg/m2 IV slowly q3wks
- Cats = 6mg/m2 IV slowly q3wks
Actinomycin D (Dactinomycin)
- Anthracendione
- strep derivative
- interacts with dsDNA in multiple ways in sequence-dependent manner. Binds ssDNA resulting in potent inhibition of transcription, thus inhibiting RNA and protein synthesis
- Passive diffusion and ABCB1 efflux
- Radiosensitizer
- 20% unchanged in urine and 14% in feces
DLT = myelosuppression and GI tox
Dosing = 0.5-0.75mg/m2 IV q1-3wks
*Vesicant
Methotraxate
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- Folate analog that inhibits dihydrofolate reductase and depletes folate sources for purine/thymidylate biosynthesis
- Active transport via reduced folate carrier cells
*Cell cycle specific = S phase
- Enterohepatic recycling – minimal excreted unchanged in urine
DLT = GI toxicity (low and high doses) and myelosuppression (high doses), mucositis
**inhibited by L-spar
Cytosine arabinoside (cytarabine, Ara-C)
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- Analog to deoxycytidine and phosphorylated in cells to generate arabinosylcytosine triphosphate (ara-CTP = active metabolite) = incorporated into DNA and inhibits function of DNA template and competitive inhibitor of DNA polymerase
- Active transport via nucleoside transporters
*Cell cycle specific = S phase
Water soluble, distributes rapidly into water and crosses BBB (CSF concentrations reaching 60% plasma level)
- Deamination by liver
DLT = myelosuppression and some GI
Dosing = 600mg/m2 CRI over 2-5 days, or
4 SQ injections BID for 2 days
Gemcitabine
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- Actively transported into cells by nucleoside transporters and phosphorylated to mono-, di-, tri- phosphorylated species which inhibits DNA synthesis
*Cell cycle specific = S phase
DLT = hematologic
Dosing = 400-800mg/m2 IV over 30-60min q7days
5-Fluorouracil (5-FU)
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- Halogenated analog of uracil
- Facilitated-transport system shared by adenine, uracil and hypoxanthine to enter cells
- intracellularly converted to active nucleotide forms to yield mono-, di-, triphosphate forms of fluorouridine and fluorodeoxyuridine = incorporated into RNA and DNA to interfere with synthesis and function
- 90% dose is metabolized and biliary excreted with <5% parent drug renally excreted
DLT = dose-dependent myelosuppression, GI tox, neurotox
Dosing = 150mg/m2 IV q7days
*CONTRAINDICATED IN CATS = SEVERE CNS TOXICITY
Rabacfosadine (Tanovea)
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- PRODRUG results in intracellular generation of nucleotide analog PMEG (guanine) = leads to cellular uptake of the parent compound and hydrolysis that leads to the generation of intracellular PMEG, which is then phosphorated and competes with dGTP as a substrate for DNA polymerase the result is incorporation into the DNA resulting in chain termination
- Preferential uptake into PBMCs and lymphoid tissue
- AE = GI, myelosuppression, elevated LE, proteinuria, derm toxicity, idiosyncratic pulmonary fibrosis
Dosing = 1mg/kg IV q21d, or q42d alternating w/ doxorubicin
Hydroxyurea
- Antimetabolite = inhibit use of cellular metabolites for cell growth and division
- Enters via passive diffusion and inhibits ribonucleotide reductase and results in depletion of deoxyribonucleotide pools and allosteric inhibition of DNA polymerase, thymidylate synthase, TK
- Cell cycle specific = Cells pass through G1/S, but accumulate in S phase
- AE = GI, myelosuppression, rarely pulmonary fibrosis, onycholysis after chronic use in dogs
Dosing = 50-60mg/kg SID x 2 weeks then 30mg/kg/d to lessen SE
Taxanes
(Paclitaxel and Docetaxel)
- Antimicrotubule agents = interfere with polymerization or depolymerization of microtubules
- Stabilize microtubules against depolymerization = inhibits reorganization needed for cell functions and leads to mitotic arrest. Yew derivative.
- Poor solubility, need excipients (cremophor EL - paclitaxel, polysorbate 80 - docetaxel) for IV admin
- AE = hypersensitivity reactions attributable to cremophor EL and polysorbate 80 formulation
DLT = diarrhea and neutropenia
Paclitaxel
- Need pretx w/ antihistamine and steroids with prolonged infusion time = 64% hypersensitivity even w/ pretx
- Dose: 165mg/m2 slow IV infusion q21d, 132mg/m2 may be better; 80mg/m2 slow infusion q21d reported in cats
*Radiosensitizer
Docetaxel
- 2x more potent than Paclitaxel
- More manageable hypersensitivity
- Indications: mammary carcinoma
Doses:
- Dog = 30mg/m2 IV over 30 min with pretreatment
- Cat = 2.25mg/kg IV over 1 hr w/ pretx
Vinca alkaloids
(Vinc, Vinb, Vinorelbine)
- Antimicrotubule agents = interfere with polymerization or depolymerization of microtubules
Vincas = bind distinct site on tubulin and inhibit microtubule assembly which disrupts mitotic spindle apparatus resulting in metaphase arrest and cytotoxicity
- Use simple diffusion
- Exposure time and concentration important for cytotoxicity
- Rapid tissue distribution with slow elimination primarily hepatic metabolism and biliary excretion of parent drug and metabolites
**Cell cycle specific = M phase
** Vesicant =
- 5-10ml saline infused around affected area and hyaluronidase can be added (150U/1mL drug)
- warm compress & DMSO and flucinolone acetonide (Synotic) mixed with 10mg flunixin meglumine applied topically after each heat application
Vinblastine
- Active metabolite = vindesine
- DLT = myelosuppression
- Doses = 2.0-2.67mg/m2 IV q7d commonly with dose escalations up to 3.0mg/m2 reported, and even up to 3.5mg/m2 IV q14d
- 1.5mg/m2 IV in cats
Vincristine
- AE = Significant ileus, less myelosuppressive, peripheral neurotoxic
- Doses = 0.5-0.75mg/m2 IV q7d or per multi drug protocol
Vinorelbine
- Indications = primary lung tumors, HS, MCT
- Radiosensitizer
- Doses =
- Dog = 15mg/m2 IV over 5 min q7d
- Cat = 11.5mg/m2
Platinums
(Carboplatin and Cisplatin)
- Activity through covalent binding to DNA (specifically purine bases) through displacement reactions resulting in bifunctional lesions and inter- or intrastrand cross-links
- Intrastrand adducts = N7-d(GpG) and N7-d(ApG) = account for majority of damage and highly correlate with cell killing
- Radiosensitizer
- Metabolism via reactions with water and elimination by binding plasma and tissue proteins
Carboplatin
- Strong correlations with exposure and renal function
- Excreted mostly through urine with 65% dose in urine 24 hours after admin
- DLT = myelosuppression
- Doses =
- Dogs = 300mg/m2 or 10mg/kg IV slowly q21d
- Cats = 200-240mg/m2 IV q21d, some need q28d due
to prolonged neutropenia
Renal function adjustment =
*Carbo dose = AUC x [(1.3 x GFR)+1.4] x BW (kg)
AUC(target) = 2.75 x mg/ml
Cisplatin
- Reactions with water are important component of pharmacology—aquated species can cross membranes more rapidly
- 50% eliminated via urine 5 days post administration
- DLT = GI and renal (requiring pretreatment with antiemetics and vigorous saline diuresis)
- Indications: OSA, TCC, mesothelioma, carcinomatosis, germinal cell tumors
- Doses = 50-70mg/m2 IV q21d
**CONTRAINDICATED IN CATS = fatal pulmonary vasculitis and edema
L-asparaginase
- Enzymatic function = hydrolysis of L-asparagine to L-aspartic acid, which depletes circulating L-asparagine = inhibition of protein synthesis in tumor cells lacking L-asparagine synthetase = induction of apoptosis
- Given SQ, IM or IP
- AE = hypersensitivity reactions can be accentuated after repeated exposures or decreased protein synthesis from depleted L-asparagine pools
- Observe patients for at least 30 min post tx and owner observation for 1-4 hours post tx for hypersensitivity
- Dosing = 400 IU/kg IM/SQ or 10,000 IU/m2 IM/SQ
