Chemo Flashcards
Which RTKs (5) does Palladia target
VEGFR2 PDGFR alpha + beta FLT3 KIT CSFR1
Which classes of drugs are considered most potentially leukemogenic?
mustard-type alkylators
nitrosurias
procarbazine
What is the aim of a Phase 0 trial?
quickly establish whether an agent displays biologic activity in humans
ie microdose PK, functional imaging
What are the aims of a Phase 1 trial?
characterize toxicity
define dose/schedule
What are the aims of a Phase 2 trial?
Detect biological efficacy
**historically, a 20% response rate was required to move to Phase III trials
What is the aim of a Phase 3 trial?
Determine if investigational tx shows statistically and clinically important benefit over accepted standard of care
What are the hallmarks of Phase 3 trial design?
Standard tx control group
Broad cohort of patients
Endpoints with relevance to patient
What characterizes first order kinetics?
log[concentration] = linear fx of time
What are Phase I reactions? Which is the most common?
Oxidation, reduction, and hydroplysis
Most common = P450 oxidation
What are Phase II reactions? Which is the most common?
Conjugation
Most common = glucuronide conjugation by UGT
What is the result of glucuronidation?
Detoxification - inactivates compound and facilitates biliary excretion
Which pharmacokinetic parameter most closely equates to toxicity?
AUC
In what form is folic acid an active coenzyme to DNA precursor synthesis, and which enzyme is required to catalyze formation of this coenzyme?
tetrahydrofolate (fully reduced)
DHFR catalyzes formation
How does methotrexate inhibit DNA synthesis?
inhibition of thymidylate synthase/ purine biosynthesis
mostly due to accumulation of inactive folate residues and dihydrofolate polyglutamates (PGs)
How does methotrexate enter the cell?
reduced folate carrier system
folate receptor
What impact do low folate conditions have on methotrexate toxicity and why?
Increased toxicity due to upregulation of folate receptors and enhanced cellular accumulation
How does leucovorin rescue work?
Overcomes enzyme inhibition by competitive displacement inactive folate PGs
Leucovorin = reduced folate; enters cell through same transport system as methotrexate
Given w/in 36hrs of treatment
How is methotrexate excreted?
active urinary secretion in proximal tubules
some biliary excretion and EH recirculation
What is the DLT of methotrexate?
GI toxicity, mucositis
What causes methotrexate-induced AKI?
MTX precipitation in acidic urine
What is the MOA of permatrexed?
TS inhibitor
What is the MOA of Pralatrexate?
DHFR inhibitor
When 5-FU is given prior to methotrexate, what impact does it have on methotrexate cytotoxicity?
Decreased cytotoxicity due to inhibition of TS by 5-FU
How does 5-FU enter the cell, and how is it activated?
Facilitated transport
Metabolized to FUDP and FUTP
What is the MOA of 5-FU cytotoxicity?
Inhibition of TS
Incorporation into RNA
What impact does methotrexate have on 5-FU activation?
Increased 5-FU activation because of increased cellular pools of PRPP
What impact do increased cellular pools of UTP and dUMP have on 5-FU toxicity?
Decreased toxicity
What impact does decreased MMR capability have on 5-FU toxicity?
Decreased toxicity
What is capecitabine?
Orally bioavailable 5-FU prodrug
5-FU has been associated with decreased clearance of which drugs?
Warfarin, phenytoin
What is the energetic equivalent of 1Gy?
1 Joule absorbed/kg tissue
In which phases of the cell cycle are cells most radioresponsive?
late G2/M
In which phases of the cell cycle are cells most radioresistant?
late S phase
What are the 5 Rs of RT?
DNA Repair cell cycle Redistribution Reoxygenation Repopulation Radiosensitization
When does accelerated repopulation occur?
After ~4wks of starting RT
What physiologic causes underly late radiation effects?
loss of stem cells
vascular changes
inflammation
**TGF-B
Which types of radiation are most likely to result in carcinogenesis?
orthovoltage
high LET
On graph of radiation dose x surviving fraction, what do alpha and beta correspond to?
a = linear component, cell death that increases linearly with dose B = quadratic component, cell death that increases in proportion to (dose)^2
On graph of radiation dose x surviving fraction, the curve for cells with a high a/B ratio appears:
Linear
On graph of radiation dose x surviving fraction, the curve for cells with a low a/B ratio appears:
Quadratic
At low-dose fractions, tissues/cells with a low a/B ratio are more or less resistant than those with a high a/B ratio?
Low a/B ratio = more resistant than high a/B ratio at low-dose fractionation schedules
Which bone is most susceptible to osteoradionecrosis?
Mandible
When do early delated effects to the CNS occur, and what do they correspond to pathophysiologically?
1-3 mo, transient demyelination
When do late delated effects to the CNS occur, and what do they correspond to pathophysiologically?
> 6mo, brain necrosis
In a large series of palliative radiation therapy for solid tumors, what was the response rate? Rate of early and late toxicity?
RR - 75%
Early tox - 60%
Late tox - 8%
In a large series of palliative radiation therapy for solid tumors, which tumor types had the highest response rate?
AGASACA - 100%
STS - 87%
OSA - 85%
Tonsillar SCC - 80%
What were the average RT dose differences for GTV and OAR as calculated on pre- and post-contrast CT?
<1%
In a study of animals dogs undergoing RT with a cobalt-60 unit, significant reduction were identified in which CBC parameters throughout treatment?
Hct, WBC, neuts, eos, monos, lymphs
In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the ORR?
67% ORR, mPFS 5.7mo
In a series of patients with various tumors treated with 5 x 4Gy PRT protocol, what was the rate of acute toxicity?
17%
In a series of 51 dogs undergoing pelvic irradiation, what was the rate of late complications? Did this impact survival?
39%, did not impact survival
Most common = skin ulceration, draining tract, colitis, strictures
Which chemotherapy drugs should be dose reduced with hepatic dysfunction?
Vinca alkaloids Paclitaxel Etoposide Busulfan Imatinib
Which chemotherapy drugs should be dose-reduced in accordance with creatinine clearance in kidney dysfunction?
Carbo/cisplatin Bleomycin Etoposide Methotrexate Hydroxyurea Topotecan
Which drugs can cause pleural effusion in cats?
Cisplatin
Docetaxel
Temozolomide
What unique toxicity does temozolomide cause in cats?
Pleural/pericardial effusion
What unique toxicity do cisplatin and 5-FU cause in cats?
Cisplatin - fatal pulmonary edema
5-FU - CNS toxicity
What antidote should be delivered following extravasation of mustargen?
Sodium thiosulfate SQ
Neutralizes mustargen to form nontoxic thioesters that are excreted in the urine
What complications may be seen with IP delivery of cyclophosphamide and vincristine in cats?
None
In dogs with OSA treated with adjuvant carboplatin, which factors were prognostic for decreased survival?
Proteinuria (pre-op)
Vascular invasion
MI >5/3hpf
Grade 3 tumors
How does the intracellular chloride concentration impact cisplatin activation?
- Cisplatin is activated by an aquation reaction, exchanging the 2 Cl leaving groups for H20
- High Cl concentration = no reaction = biologically inactive
- Intracellular concentrations of Cl are LOW compared to extracellular, so equation proceeds once cisplatin enters the cell
How does iohexol clearance correlate with carboplatin clearance?
Linear correlation
Which drug is more protein-bound: carboplatin or cisplatin?
Cisplatin > carboplatin protein binding
What is the DLT for idarubicin?
neutropenia, thrombocytopenia
What concerns arise with the use of denamarin and CCNU together?
Chemoresistance - SAMe and silybin are both potent antioxidants
Which of the following chemotherapy drugs may be detected in the urine up to 7d after administration? CYC Vincristine Vinblastine DOX
Vinblastine
DOX (up to 21d)
What is the Calvert formula for carboplatin reduction?
Dose (mg) = target AUC x [GFR+25]
What is the recommended (weekly) starting dose of vinorelbine in dogs and cats? What are the DLTs?
Dogs - 15mg/m2; DLT = neutropenia
Cats - 11.5mg/m2; DTL = neutropenia, vomiting, nephrotoxicity? (AKI in one cat)
What is the MTD of VBL when combined with 3.25mg/kg toceranib EOD?
1.6mg/m2 q2wk
How did the response rate and toxicity of a multiagent chemotherapy protocol with epirubicin compare to that of CHOP?
RR was equivalent/superior to previously published for CHOP
toxicity was less than previously published for CHOP
What is the MOA of suramin?
Antiparasitic that inhibits reverse transcriptase and blocks growth factors
In a patient with renal and liver dysfunction, which of the following drugs could you administer without risk of increased toxicity?
methotrexate, vinca, DOX, mustargen, platinum
Mustargen (undergoes spontaneous hydrolysis)
Metabolized by liver: vinc, DOX
Excreted/potential for kidney damage: platinums
What drugs can be used in the case of liver failure?
Mustargen, fluorouracil, CYC
+/- oxalaplatins
NO taxanes, vincas anthracyclines, or ironotecan
Which drugs rely more on AUC than Cmax for efficacy?
Gemcitabine, Cytosar
What activates cisplatin?
Aquination (interaction with water)
Genetic polymorphisms in what gene can impact 5-FU toxicity, and why?
Dihydropyrimidine dehydrogenase (DPD) - catalyzes rate limiting step in 5-FU clearance
In a drug with first order pharmacokinetics, what happens to drug clearance as drug concentration increases?
Clearance increases linearly
In a drug with “zero order” pharmacokinetics, what happens to drug clearance as drug concentration increases?
Clearance remains the same - saturable clearance mechanism
What are the characteristics of cisplatin nephrotoxicity?
dose dependent acute tubular necrosis with azotemia and hypomagnesemia
What class of drugs does upregulation of MGMT increase resistance to?
Alkylators
What are the mechanisms of resistance to cisplatin?
Inactivation by glutathione
Increased NER
Decreased MMR
Which alkylators are bifunctional?
Melphalan
Chlorambucil
Cyclophosphamide/Ifosfamide
Mustargen
Which alkylators are monofunctional?
CCNU
Dacarbazine
Procarbazine
Streptozotocin
Does MESNA prevent ifosfamide-induced nephrotoxicity?
No - only cystitis by binding acrolein in the urine
How is ifosfamide activated?
P450 activation in liver - does NOT require intracellular activation
What metabolite of ifosfamide is neurotoxic?
Chloracetaldehyde - unique to ifosfamide
Which of the vincas has the highest tubulin affinity?
Vincristine
Inhibits tubulin polymerization even at very low concentrations
Also results in greater toxicity
Which topoisomerase isoform do epipodophylotoxins inhibit?
Topo-II
Etoposide & tenoposide = topoisomerase II inhibitors
What is the rate of docetaxel hypersensitivty in cats?
20% - ONLY when given IV (not when given orally), generally mild
What is the DLT of docetaxel in cats?
myelosuppression, GI
Why are cyclosporine and docetaxel given together?
CSA increases bioavailabilty of PO docetaxel
What is the DLT of satraplatin?
myelosuppression
thrombocytopenia occurs BEFORE neutropenia
GI tox was mild
Which of the following is more specific for kit inhibition?
Masitinib
Toceranib
Masitinib
Which of the following does masitinib inhibit with more efficacy?
WT kit
mutant kit
Inhibits both with similar efficacy
How might masitinib reverse DOX resistance?
Inhibition of PGP
Which four receptors does masitinib inhibit?
Kit
PDGFR
Lyn
FGFR
Which 3 receptors does imatinib ihibit?
BCR-Abl (ATP binding pocket of Abl)
Kit
PDGFR-alpha
What does bevacizumab bind?
VEGF
does NOT inhibit VEGFR directly
What is decitabine?
DNA methyltransferase inhibitor –> HYPOmethylating agent
May cause tumor progression due to genomic instability
How might decitabine increase wt-p53 expression?
Decitabine = hypomethylating agent
Removes inhibitory methylation of p53 promoter
Other than vincas and taxanes, which drugs inhibit the mitotic spindle?
Griseofulvin
Colchicine
What are Polo-like kinases (Plks)?
regulatory serine/threonine kinases involved in cell cycle:
mitotic entry, mitotic exit
spindle formation
cytokinesis, meiosis
Name 3 mitotic kinases.
Aurora
Polo-like
Bub
What impact does L-spar have on methotrexate?
Inactivation
How does rapamycin inhibit mTOR?
inhibits phosphorylation of AKT by direct binding to mTOR
What is the target of farnesyl transferase inhibitors?
HRAS inhibition
Farnesyl transferase inhibitors prevent post-translational modification of Ras
Aminobisphosphonates bind strongly to hydroxyapetite at which site?
R1, N1, R2, N2
R1
What is the active form of ara-C, and how is it activated?
ara-CTP
activated intracellularly by phosphorylation
How is ara-C catabolized?
intracellular deactivation by cytidine deaminase to ara-U
Which two drugs are metabolized/inactivated by cytidine deaminase?
cytosar and gemcitabine
What impact does loss of ATR and Chk1 have on ara-C toxicity?
loss of ATR and Chk1 = increased ara-C toxicity
ATR and Chk1 block cell cycle progression and allow DNA repair
Ara-C is lipid or water soluble?
Water
With which agents is ara-C synergistic?
alkylating agents
methotrexate
etoposide
While GI toxicity and myelosuppression are the DLTs for ara-C, what unique toxicities can be seen with high-dose regimens?
Pulmonary toxicity
Cholestatic jaundice
Cerebellar toxicity
What are the mechanisms of action of ara-CTP?
Inhibition of DNApol-alpha
Incorporation into DNA
Termination of DNA chain elongation
What is the MOA of 5-Aza-Cytidine analogs such as aza and decitabine?
incorporate into DNA and inhibit DNA methylation
aka hypomethylating agents
What is the active form of gemcitabine, and which enzyme catalyzes the first step of this reaction?
dFdCMP
CdR catalyzes first phosphorylation step
What is the MOA of gemcitabine?
Inhibits DNApol & DNA repair
Incorporates into DNA
**Inhibits ribonucleotide reductase (this is where it differs from ara-C)
Which facet of gemcitabine MOA is implicated in its activity as a radiosensitizer?
Ribonucleotide reductase inhibition
How are gemcitabine and ara-C eliminated?
deamination in liver, plasma, and peripheral tissues by cytidine deaminase
What class of drug is 6-mercaptopurine?
Purine antimetabolite
Why does concurrent use of allopurinol increase 6-mercaptopurine bioavailability
Inhibits xanthine oxidase
6-MP is metabolized by intestinal xanthine oxidase, leading to significant first-pass effect
Which of the guanine analogs carries the highest risk of hepatotoxicity?
thioguanine
How is 6-mercaptopurine eliminated?
metabolism by xanthine oxidase and TPMT
How is thioguanine eliminated?
Hepatic metabolism
What is the MOA of 6-MP and thioguanine?
Incorporation of “fraudulent” nucleotides into DNA
6-MP also inhibits de novo purine synthesis
What is the MOA of fludarabine?
adenosine analog that incorporates into DNA
What is the MOA of pentostatin?
inhibition of adenosine deaminase –> accumulation of dATP
What is unique about the activity of cyclophosphamide and ifosfamide in relation to other alkylating agents?
Require metabolic activation by P450
What is the first step of the alkylation reaction?
Chlorine leaving group is lost, resulting in formation of reactive aziridinium ring
What DNA location do melphalan, busulfan and mechlorethamine alkylate?
N-7 guanine
melphalan also does adenine N-3
What DNA location do the nitrosureas, procarbazine, and DTIC alkylate?
O-6 methyl group of guanine
Which alkylators are bifunctional nitrogen mustards?
Meclorethamine Melphalan Chlorambucil Cyclophosphamide Ifosfamide Bendamustine
Which alkylators are monofunctional nitrosureas?
CCNU
BCNU (carmustine)
atypical alkylators (procarb, DTIC) are most closely related to nitrosureas
Characterize the lipid solubility and CNS penetration of procarbazine and DTIC?
Highly lipid soluble, penetrate CNS
How are most alkylating agents degraded?
Hydrolysis of alkylating moiety
aka alkylation of water
What accounts for the slow entry of bleomycin into cells?
Large size, cationic (charged)
Which drugs inhibit topoisomerase I?
topotecan & ironotecan
Does one- or two-electron reduction of DOX result in a more toxic metabolite?
One-electron reduction –> semiquinone radical
Two electron reduction results in an unstable compound that spontaneously degrades into less toxic metabolites
What interaction is expected between anthracyclines and PARP inhibitors?
Antagonism
What impact does genetic deficiency of thiopurine methyltransferase (TPMT) have on sensitivity to mercaptopurine and 6-TG?
Increased toxicity in individuals with TPMT deficiency
What is the primary toxicity of the guanine analog nalaabine?
Neurotoxicity
What is the MOA of hydroxyurea?
Inhibition of ribonucleotide reductase - this enzyme catalyzes the rate-limiting step in dNTP synthesis
Inhibition occurs via iron chelation and inactivation of tyrosyl radical
To which cell-cycle phase is the cytotoxic activity of hydroxyurea specific?
S phase
As part of its catabolism, hydroxyurea is converted to what potent ribonucleotide reductase inhibitor?
Nitric oxide
What enzyme is responsible for hydroxyurea degradation?
urease
What is the DLT of hydroxyurea?
myelosuppression
What is the oral bioavailability of hydroxyurea?
80-100%
What is the route of elimination of hydroxyurea?
Renal
Name 3 biological actions of vinca alkaloids outside of microtubule interaction?
Interference with:
- Amino acid transport
- DNA/RNA synthesis
- Protein/lipid metabolism
At what point do vincas and taxanes block mitosis?
metaphase/anaphase transition
What occurs at low and high concentrations of vinca alkaloids?
Low conc = interference with microtubule dynamics
High conc = inhibits polymerization of tubulin
Rank the vinca alkaloids in order of their binding affinity for tubulin.
Vincristine > VinBLAstine > Vinorelbine > VFL
**does NOT determine antitumor activity, but does appear to correlate to neurotoxicity
Name 3 tissues in which ABCB1 is constitutively expressed?
Renal tubular epithelium, colonic mucosa, adrenal medulla
Which of the vinca alkaloids has the longest terminal half-life?
Vincristine
What is the route of elimination for all vinca alkaloids?
Hepatic metabolism and biliary excretion
Characterize the degree of binding of vinca alkaloids to plasma protein and blood elements such as platelets?
Highly protein-bound
Bind plt and other blood elements with high affinity
What alterations in tubulin can result in resistance to vinca alkaloids?
Structural alterations in alpha and beta tubulin resulting in increased stability Decreased expression of class III B tubulin
In which organ does vincristine accumulate to the greatest extent?
Spleen
What % of vincristine/metabolites is excreted in the urine?
~12%
Which of the following drugs is more extensively concentrated in tissues: vincristine or vinblastine?
vinblastine
Which of the vinca alkaloids is most lipophilic?
vinorelbine
What impact might concurrent treatment with erythromycin or itraconazole have on vincristine toxicity?
Increased toxicity due to CYP3A inhibition
What impact do taxanes have on intracellular tubulin concentration?
Decreased tubulin concentration due to stabilization of polymerized tubulin
Which of the ABC transporters is most important in conferring taxane resistance?
MDR1
What steps should be taken in the case of vincristine extravasation?
Heat/warm packing
SQ hyaluronidase injection
What impact can L-spar have on vincristine clearance?
Decreased hepatic clearance –> increased toxicity
What is considered the DLT of vincristine? Of the other vincas?
vinc - neurotox
others - myelosuppression
Characterize the degree of protein binding by taxanes.
Highly protein bound
What impact do increased levels of the beta-III tubulin isotype have on sensitivity to vincas and taxanes?
Taxanes - increased resistance
Vincas - increased sensitivity
B-III tubulin increases dynamic instability
For which of the following is the affinity of taxanes higher?
a) soluble tubulin
b) polymerized tubulin
Polymerized tubulin
Where is the primary taxane binding site?
N-terminal of B-tubulin subunit
What factors limit oral bioavailability of taxanes, and coadministration of which drug may help mitigate this?
Pgp/first-pass metabolism by liver/enterocytes
Cyclosporine can help improve oral bioavailability
What cardiac symptoms are most commonly observed in association with taxane treatment?
Bradyarrythmias
How are taxanes eliminated
P450 metaboism and biliary/fecal excretion
<10% in urine
MRP1 and MRP2 (ABCC1 and ABCC2) are more important in resistance to which of the microtubule-targeting agents?
Vincas
Limited contribution to taxane resistance
What is the DLT of paclitaxel?
neutropenia
Which infusion schedules increase the risk for paclitaxel-associated neurotoxicty?
short infusion schedules
What impact do mutations in KRAS or BRAF have on sensitivity to anti-EGFR therapies?
Decreased sensitivity - downstream activation
What were the two characteristics proposed as “emerging” hallmarks of cancer in Hannahan and Weinberg’s 2011 review of the hallmarks of cancer?
Deregulated cellular energetics
Avoiding immune destruction
What were the original 6 characteristics proposed as the hallmarks of cancer?
sustaining proliferative signaling evading growth suppressors enabling replicative immortality activating invasion and metastasis inducing angiogenesis resisting cell death
What is a nucleophile?
Electron-rich atom
If a tumor shows resistance to a nitrogen mustard agent such as CYC, will it also exhibit resistance to a nitrosurea such as CCNU?
Not necessarily - nitrogen mustards and nitrosureas show only partial cross-resistance
Alkylation by alkylating agents is nonuniform along the length of the DNA strand. Which areas of DNA are most vulnerable to alkylation?
Regions of active transcription
Name two mechanisms of resistance with relevance to all alkylators?
glutathione inactivation
enhanced DNA repair - esp DNA alkyltransferase
Decreased MMR results in decreased sensitivity/increased resistance to which classes of drugs?
5-FU
alkylators
methylators (DTIC, procarb)
platinums
What are the most common adducts formed by alkylating agents?
N3 methyladenine
N7 methylguanine
What effect does increased BER function have on tumor cell sensitivity to alkylators?
Decreased sensitivity
What impact does xeroderma pigmentosum have on sensitivity to alkylating agents?
Increased sensitivity
Xeroderma pigmentosum = defective NER
What happens to cyclophosphamide metabolism and half-life over time (increases or decreases) with ongoing administration?
Metabolism increases, half-life decreases - both CYC and ifosfamide induce their own metabolism by P450 enzymes
How does 2-mercaptoethane sulfonate help to prevent acrolein-induced cystits without impacting anti-tumor activity?
MESNA dimerizes to inactive metabolite in plasma and hydrolyzes in urine to conjugate with acrolein
Name 3 features common to all atypical alkylators/methylating agents (ie procarb, DTIC).
lack bifunctionality
prodrugs that require activation
contain N-methyl group
Name 2 mechanisms of resistance that impact sensitivity to all methylating agents.
AGT-mediated O6 methylguanine repair
MMR deficiency
What impact does the activity of AGT have on sensitivity to procarbazine? CCNU?
Decreased sensitivity/increased resistance
AGT functions in O6 methylguanine repair - increases resistance to methylators and nitrosureas
By what route are procarb and DTIC eliminated?
Renal excretion
What is the common metabolite generated by both DTIC and temozolamide under physiologic conditions?
MTIC –> AIC
Which of the atypical alkylators penetrate the BBB?
Procarb
Temozolomide
NOT dtic
What is the oral bioavailability of CYC, melphalan, and busulfan?
CYC - 100%
melphalan - 30% (variable)
busulfan >50%
What proportion of CYC, ifosfamide, and melphalan is excreted into the urine unchanged?
CYC/ifos - NONE - only inactive oxidation products excreted
Melphalan - 20-35%
What is the DLT of IV procarbazine? What is the efficacy of IV procarbazine compared to oral dosing?
DLT = neurotoxicity
Lack of efficacy due to need for first-pass metabolism and drug activation
To what extent is DTIC protein-bound in plasma?
~20% loosely protein-bound
What percentage of DTIC is eliminated unchanged in the urine?
~50%
How is temozolomide converted to its active metabolite?
Spontaneous conversion on interaction with water, especially at alkaline pH >7.0
Which enzyme constitutes the primary mechanism of resistance to temozolomide?
AGT
Cisplatin’s chloride leaving group is much simpler than that of carbo or oxaliplatin – what impact does this have on its reactivity, passage through membranes, and toxicity relative to other platinum drugs?
Greater reactivity in aqueous solution
Crosses membranes more readily
Greater toxicity
Platinums have higher affinity for which nucleic acid? Interactions with DNA or RNA account for most of their cytotoxicty?
higher affinity for RNA, but most toxic effects come from DNA
What is the predominant DNA repair pathway used to repair platinum-induced DNA lesions?
ds break repair (ie NHEJ, HR)
What is amofostine?
A disulfide preferential activated in normal cells to scavenge free radicals – can be used to prevent cisplatin-associated neurotoxicity.
What is the preferred solution for cisplatin injection?
normal saline
**avoid Mg++ containing fluids and aluminum needles as these mat inactivate cisplatin
What is the Calvert formula for carboplatin dosing?
dose = target AUC * (GFR + 25)
What DNA lesions are formed by platinums?
Bifunctional DNA adducts which result in kinking of DNA due to rigid bond angles
What DNA lesions does bleomycin result in?
Direct DNA damage –> intercalation, ss and ds breaks
In which phases of the cell cycle is DNA most sensitive to cleavage by bleomycin?
G2/M, and G1
Is bleomycin a substrate for Pgp/MDR1?
no
How is bleomycin excreted?
Urinary
Name 3 factors that increase risk for bleomycin-induced pulmonary toxicity.
- previous RT to chest
- cumulative dose >450U
- renal dysfunction
- age
Which cytokines are implicated in bleomycin-induced pulmonary toxicity?
TGF-B
TNF-a
IL-1B
IL2, 3, 4, 5, 6
How does anthracycline dosing schedule impact efficacy? Toxicity?
No impact of dosing schedule on efficacy - this depends on AUC
Shorter infusion times –> greater toxicity - this depends on Cmax
What is the MOA of dactinomycin?
inhibition of RNA & protein synthesis by binding to DNA
Is dactinomycin a substrate for Pgp?
Yes
What is the MOA of topotecan and ironotecan?
Topo-I poison - stabilizes cleavable complex
What is the DLT of topotecan and ironotecan?
neutropenia, thrombocytopenia
GI/diarrhea - ironotecan»_space;> topotecan
What impact does an acidic microenvironment have of cell entry of DOX?
Acidic env’t –> DOX becomes ionized
If EC acidosis –> ionization and accumulation outside cell
If IC acidosis –> accumulation within cell
How is mechlorethamine degraded?
Spontaneous degradation
What are the steps in CYC metabolism?
Activation in the liver to 4-OHCP
Spontaneous reversible ring opening to aldehyde aldophosphamide
Spontaneous irreversible breakdown of aldophosphamide to phosphoramide mustard and acrolein
What is the most active CYC metabolite?
Phosphoramide mustard
What is the major difference between CYC and ifosfamide metabolism, and how does this relate to toxicity?
Decloroethylation occurs much more frequently in ifosfamide (up to 25%) –> formation of neurotoxic choroacetaldehyde
What is the primary metabolite of chorlambucil?
phenylacetic acid
Why is DTIC use discouraged in cats?
Lack of information regarding their ability to convert the drug to active form
What percentage of dactinomycin is excreted unchanged in urine and feces?
20% urine
14% feces
What do one- and two-electron reduction of DOX result in?
One-electron reduction –> semiquinone free radical –> H2O2
Two-electron –> less toxic metabolites
Why is the activity of dexrazoxane increased in cardiac myocytes compared to other tissues?
greatly increased conversion of prodrug to active iron chelator
What impact do increased Bcl-2 expression and NFkB expression have on DOX sensitivity?
Decreased sensitivity/ increased resistance due to resistance to apoptosis (Bcl-2) and improved cellular response to stress (NFkB)
DOX is a substrate for which efflux pumps?
MDR1
MRP
What is the primary mode of DOX excretion?
Biliary
What impact does paclitaxel administration have on DOX clearance?
delayed, likely due to Cremophor which is a substrate for Pgp
What impact does coadministration of traztuzumab have on risk for DOX-induced cardiotoxicity?
increased risk
What is the most cardiotoxic metabolite of DOX?
Doxorubicinol
How do anthracyclines enter the cell?
Diffusion of un-ionized drug
What impact does reduction in topoisomerase II activity have on DOX resistance?
decreased topo-II activity –> increased resistance to DOX & other topo-II inhibitors
What impact would increased cellular levels of topoisomerase II have on sensitivity to etoposide?
Increased sensitivity
What type of DNA breaks do topoisomerase I and III result in?
ssDNA breaks (Type I topoisomerases)
What type of DNA breaks does topoisomerase II result in?
dsDNA breaks
What change in etoposide dosing should be made in patients with renal dysfunction?
dose decrease - ~40% etoposide is eliminated by kidneys
Does etoposide function as a radiation sensitizer?
yes
What is the result of coadministration of etoposide and platinum drugs?
Highly synergistic
L-spar catalyzes hydrolysis of asparagine to which end products?
aspartic acid + ammonia
What impact does L-spar have on methotrexate activity?
terminates action of methotrexate
What is the MOA of first-generation bisphosphonates such as etidronate and clodronate?
metabolized to cytotoxic analogs of ATP
What is the MOA nitrogen-containing bisphophonates (risendronate, pamidronate, and zolendronate)?
- inhibit farnesyl diphosphate synthase, a mevalonate pathway protein, decreasing prenylation of essential GTP-binding proteins
- increase osteoblast secretion of an inhibitor of osteoclat recruitment
- increase osteoblast secretion of TGF-B, a signal for osteoblast apoptosis
Which side chain determines bisphosphonate antiresorptive potency?
R2 side chain
Characterize the oral bioavailabiltiy of bisphosphonates.
Poor (<1%) due to calcium binding
How are bisphosphonates metabolized and excreted?
they are NOT metabolized - P-C backbone is resistant to hydrolysis
excreted through kidneys
What accounts for bisphosphonate binding to hydroxyapetite?
R1 side chain
What deterines bisphosphonate-induced renal toxicity?
R1 side chain - related to high total dose, short infusion time, and decreased baseline renal function
Which drugs are substrates for all 3 major drug efflux pumps (Pgp, MRP1, and BCRP)?
DOX/daunorubicin
methotrexate
Vincristine, vinblastine, etoposide and paclitaxel are substrates for which drug efflux pumps?
Pgp
MRP1
For which drug efflux pumps is mitoxantrone a substrate?
Pgp
BCRP/ABCG2
What is the target of lapatinib?
HER2 + EGFR
Which targeted therapy are nonsmoking women (especially those of Asian decent) with lung carcinoma most likely to respond to?
EGFR inhibitors - gefitinib and erlotinib
What is the target for rapamycin?
TORC1
What is the target of sorafenib?
RET, VEGFR
Which family of kinases are the primary effectors of inflammatory cytokine receptor signaling?
JAK
JAK2 inhibitors are used in myeloproliferative diseases in people
What is the target of crizotinib?
ALK (anaplastic lymphoma kinase)
Activating point mutations in which gene result in the hereditary multiple endocrine neoplasia type 2?
RET
What is ipilimumab?
anti-CTLA-4 mAb
What toxicities limited the utility of hyaluronan cisplatin nanoconjugate in dogs with SCC?
Severe myelosuppression, cardiotoxicity, and ALT elevations
What was the DLT of oral PPARg agonist rosiglitazone?
hepatic - ALT elevation
What does formulation of therapeutic proteins with polyethylene glycol (PEG) achieve?
Increased circulating half-life
Decreased immunogenicity
What was the MTD of PEGylated TNFa in dogs with various tumors?
26.7 ug/kg
DLT = vascular leak, hypotension, coagulopathy
minor/transient tumor responses noted in various tumor types
What is valproic acid and what can be used as a pharmacodynamic biomarker for its activity?
HDACi
histone hyperacetylation in circulating PBMCs
**valproic acid was well tolerated in dogs, MTD not reached
What clinical factors were associated with prolonged hospital stay in febrile neutropenic canine chemo patients?
tachycardia at admission
comorbidities
G-CSF use
decreasing neutrophil count after admission
What was the mortality rate and what factors were associated with death in-hospital in febrile neutropenic canine chemo patients?
8.5%
hypotension, G-CSF use
What was the rate of GI toxicity & creatinine elevation from baseline in dogs receiving piroxicam? Which factors increased risk of these toxicities?
GI - 84% - age and GI protectants increased risk
Creat - 73% - TCC increased risk
What was the incidence of SHC after CYC given orally over 3 days?
0%
historical values - 11% for single dose, 1.4% for single + furosemide
Increased LEs occurred in what %s of dogs receiving CCNU alone vs CCNU with denamarin?
84% vs 68%
dogs w/o SAMe had significantly greater increases in liver values and were more likely to have tx delayed or discontinued
What was the response to plasmid GHRH electroporation to treat cancer-associated anemia in dogs?
Up to 54% had increased Hct, and responders had significantly longer survival
How long is platinum detectable in canine urine, feces, saliva, sebum, and cerum by mass spec following administration?
at least 21 d
What was the MTD of vinorelbine in cats?
11.5mg/m2
What % of cats were euthanized due to toxicity in a pilot study of temozolomide +/- DOX?
40% :(
1 due to prolonged myelosuppression, 1 due to pleural/pericardial effusion (apparently cumulative toxicity >1300mg/m2)
What was the rate of hepatotoxicity in cats treated with CCNU?
6.8%
What proportion of cats had DPD activity values indicating decreased activity? Is decreased DPD activity thought to account for unique 5-FU toxicity in this species?
23% - not thought to account for 5-FU tox
In another study, 14% of dogs with abnormal
What was the rate of AEs in a large series of dogs treated with epirubicin?
36% of treatments
What is the MTD of idarubicin in dogs >15kg?
22mg/m2
What was the RR of epithelial neoplasia to oral docetaxel + CSA?
17%
50% RR for OSCC
What is the MTD of Paccal Vet in dogs?
150mg/m2
Dogs with MCT treated with Paccal Vet were ___x more likely to have a response than those treated with CCNU?
6.5X
RR = 7% (23% BRR)
What was the MTD of a single bolus gemcitabine dose in dogs?
900mg/m2
Undetectable in urine at 24hrs
Metronomic CCNU was discontinued in what % of patients due to toxicity? When was hepatotoxicity recongized?
27%
hepatotox at median 11d
What % dogs developed hypertension following treatment with Palladia?
37%
What was the MTD of CCNU + Palladia?
50mg/m2 q3wks
What is the MTD of toceranib + piroxicam?
Full dose of both
What was the ORR of canine MCT to toceranib + VBL?
71%
Which combinations of bisphosphonates and chemotherapy drugs elicited synergistic killing in histiocytic sarcoma cell lines?
clodronate + vinc
zol + DOX
What is the genotype of the ABCB1 polymorphism in dogs?
4 base-pair deletion resulting in a reading frame shift and premature stop codons
Other than the BBB, what privileged sites does PGP participate in maintaining?
blood-testes barrier
placenta
Other than the BBB, what privileged sites does BCRP (ABCG2) participate in maintaining?
retina - this is thought to underly fluoroquinolone-induced blindness in cats
What is the function of feline ABCG2 compared to humans?
decreased
What is the MTD of DOX in horses?
75mg/m2 q3wks
DLT = hypersensitivity and neutropenia