Professional Documents
Culture Documents
Table of Contents:
Overview of pharmacology ........................................................................................................................................2
Drugs and enzymes.....................................................................................................................................................3
Receptors: Targets for Drug Action ............................................................................................................................4
Drug Metabolism ........................................................................................................................................................6
Principles of drug development .................................................................................................................................8
Complementary & alternative medicines ............................................................................................................... 10
Molecular Imaging ................................................................................................................................................... 11
Pharmacokinetics .................................................................................................................................................... 12
Autonomic Pharmacology I - Parasympathetic ....................................................................................................... 16
Autonomic Pharmacology II - Sympathetic ............................................................................................................. 19
An Overview of Cancer Chemotherapy ................................................................................................................... 23
Principles of antibody therapy for cancer ............................................................................................................... 26
Mechanisms and uses of antimetabolite drugs, signal transduction inhibitors, and anti-angiogenesis drugs in
antineoplastic therapy............................................................................................................................................. 28
Cancer Chemoprevention........................................................................................................................................ 32
Antineoplastic alkylating agents and platinum compounds ................................................................................... 34
DNA Topoisomerase-targeted drugs and mitotic spindle poisons .......................................................................... 39
1
Overview of pharmacology
Egyptians had all kinds of prescriptions: active constituents, carriers, formulations, deliveries.
Greeks & Romans used drugs like juniper oil (diuretic & abortifacient). Homer described opiates, Socrates took
hemlock (glycine receptor agonist), Hippocraties didn’t like drugs, and Pedanius discordies (physician for Nero)
wrote about 900+ drugs. Claudius Galenius made one of the best discoveries: don’t use urine & feces as drugs,
but also advocated polypharmacy (which didn’t work, so people stopped studying drugs)
16th-18th c.: Ascorbate (vit. C) for scurvy , Quinine for malaria, Digitalis for dropsy (=CHF edema) from foxglove.
Modern approaches:
1. Natural products – through 1960, usually studying extracts’ effects on animals or disease models, and
then purifying compounds to study (in vivo / cellular, etc.). Analogs then synthesized & optimized
2. Drug target screens with synthetic compounds – “magic bullets” (Ehrlich’s approach, 1900-present).
Screen compounds against organisms / receptors / enzymes & use “hits” as basis for more specific /
potent analogs. E.g. salvarsan for syphilis. Precursor of combinatorial chemistry
3. Rational drug design (1970-present). Examine molecular target (protein target, ligand, substrate) &
design high affinity molecules (e.g. ACE inhibitors, protease inhibitors). Manipulate synthetically as
needed.
4. Biotechnology (1980-present). Genetically engineer proteins (e.g. recombinant insulin), monoclonal Ab
(e.g. rituximab), maybe gene therapy in the future.
Challenges:
Few well-validated human gene targets identified
Need “blockbusters” for big pharma to invest
Need to expand “chemical space” (more new classes of drugs)
Need rational approaches to ADME (absorption, distribution, metabolism, excretion)
2
Drugs and enzymes
Graphing:
You can plot [AX] vs [X] (e.g. velocity vs.
substrate, response vs. drug, binding vs.
receptor) and get a saturated curve
(rectangular hyperbola). If you use
log([X]), you get a sigmoid curve (semilog
plot).
The point where you’re at half max (inflection in semi-log plot) goes by different names: Km for enzyme,
Ki for inhibitor, ED50 for drug, Kd for receptor binding. But it’s all the same – a measure of how the
thing you’re analyzing works & at what concentration it’s effective.
If you vary the enzyme or target, when you’ve got a high amount of substrate, you see zero order
kinetics (e.g. the amount doesn’t matter because you’re usually saturated).
In a rectangular hyperbola example, you’re usually in zero order situations at the point of saturation –
you’re processing a constant amount of something per unit time.
When you’re in the linear early part of the curve, you’re in first order kinetics: processing a constant
percentage per unit time.
Inhibitors:
Competitive inhibitors change Km, not Vmax (changing how well it binds, but can be overwhelmed by
more drug). Efficacy is the same (maximum effect)
Noncompetitive inhibitors change Vmax, not Km (same binding, just taking some enzyme out of
picture). Efficacy is lowered.
So look at the graph: is Vmax changing? Then it’s noncompetitive. Is Km changing? Competitive.
Potency means you can get the same effect if you just use more of a dose (effect per dose)
Scatchard plot has drug bound/ drug free on Y axis, drug bound on X-axis.
The x-intercept is Bmax, the highest amount of bound drug possible.
The slope is -1/Kd
Scatchard plot and Eadie-hofstee plots are reciprocals of the same graph.
Kinetics: first order rate means that a constant % is removed per unit time. 𝐷𝑡 = 𝐷0 𝑒 −𝑘𝑡
Example: ethanol. One of very few substances that gets into zero order metabolism (constant amount) because
you ingest in grams scale.
3
Receptors: Targets for Drug Action
Occupancy theory: biological effect (E) proportional to the concentration of the receptor-ligand complex ([RL])
4
Apply to receptor with no ligand Apply to receptor along with ligand
Agonist Full effect (stimulation) No effect
Antagonist No effect Full effect (inhibition)
Partial agonist Partial effect (some stimulation) Partial effect (some inhibition)
Ligand Binding
Use labeled (radiolabeled) ligand
Vary ligand concentration [Lt]
Measure receptor-bound ligand concentration
([RL]) and free ligand concentration ([L])
Plot as either rectangular hyperbola or
scatchard plot (RL/L vs RL on linear scale)
where slope = -1/KD, intercept = Bmax (Rt)
o Steeper line = higher affinity
Receptors: can belong to different families; ligand binding & effector domains usually linked. Subtypes exist for
most ligands (hormones, neurotransmitters, drugs). Subtypes can have different downstream effects & patterns
of expression (in different tissues or at different times in development.
5
Drug Metabolism
Drug metabolism: generally producing more polar / water soluble conjugates (better excretion). Can sometimes
make more active/toxic compound
Liver is key for majority of drug metabolism.
Important for:
Toxicity: sometimes you can generate toxic/teratogenic metabolites (e.g. thalidomide)
Activity: metabolites can be active (e.g. terfenadine)
Drug interactions (inhibition of metabolism): another drug can increase to toxic levels (e.g.
ketoconazole and terfenadine)
Drug interactions (induction of metabolism): another drug can decrease to sub-therapeutic levels (e.g.
rifampin and oral contraceptives)
Almost no oral drugs are absorbed in stomach. Most absorbed in small intestine like food & have to pass
through portal circulation to the liver (makes sense – want to detoxify them first.)
First-pass metabolism: metabolism that drug goes through in that first pass through the liver (before reaching
systemic circulation / “central compartment”)
“high extraction”: drugs that are taken up & heavily metabolized by hepatocytes during first pass; their
hepatic clearance is dependent on liver blood flow
“low extraction”: negligible first-pass effect
How to circumvent:
o Change the route of delivery (IV, sublingual, transdermal, rectal – distal colon to IVC)
o Change the rate of metabolism (co-administer inhibitor of metabolism)
6
o Can inhibit one or several classes of P450s
o Major offenders: cimetidine (anti-ulcer), macrolide antibiotics (erythromycin), antifungal azoles
(ketoconazole)
o Example: terfenadine levels increase if administered with ketoconazole; original form of drug
causes arrhythmias (before metabolized)
P450 Inducer: Any drug that causes increased production of enzymes responsible for the metabolism or
biotransformation of another drug (drug acts as promoter, increases transcription)
o Increased mRNA levels (drug binds to enhancer elements upstream from enzyme coding region)
o Major offenders: phenobarbitol (anticonvulsant); rifampin (antibiotic) – e.g. with contraceptives
Neonates: low levels of functional glucuronosyl transferases (until ~1 mo) – can be particularly susceptible to
toxicity from toxins & drugs that are inactivated / cleared through glucuronidation
Elderly: can have reduced liver blood flow / reduced Phase I capacity (underlying disease, aging)
Cirrhosis can affect drug clearance via 2 mechanisms
o Liver fibrosis (reduced blood flow through portal circulation: less 1st pass effect, higher systemic
concentrations of parent drugs
o Decrease in functional hepatocytes = less phase I capacity (mostly late in liver dz)
Phase I reactions: impaired in acute & chronic liver disease;
Phase II (conjugations) usually only in end-stage liver disease
7
Principles of drug development
Five major players: pharma, regulatory agencies (FDA), consumers, academia, legislature)
History of drug development: chance observation trial and error targeted screening (Ehrlich’s “magic
bullet”, pasteur’s “anti-bodies” & “lock & key” model)
Discovery vs Development
Discovery: identify the “lock”, develop a pattern of chemical “keys”, rapid-throughput screening, in vitro
or in vivo model systems – or can exploit a chance observation (still possible)
Development: getting the drug discovered, through the system & to the patient.
o 15-20% of overall health care expenditures, but changes from year to year (can regulate – and
there’s a trade-off with savings from reduced hospital days / morbidity / mortality)
o $420B in 2005; increasing market for generics (2/3 Rx in 2009) and worldwide
1:30,000 chemicals licensed drug
1:10 drugs in clinical testing licensed drug
1:5 licensed drugs covers R&D expenditure
o Costs ~ $1B and patent life is 8-10 years so need $50-100M/year
o So pharma focuses on blockbusters (high use & profitability – prevalent chronic conditions)
Phases of drugs
Pre-clinical drug development
o Efficacy, mechanism of action, toxicology
o Pharmacokinetics (ADME) – Absorption, Distribution, Metabolism, Excretion
o Pharmaceutics (formulation development)
Phase I: short-term safety & tolerability; pharmacokinetics
o 10s of healthy volunteers; days to weeks
Phase II: medium-term safety and tolerability; initial evidence of beneficial activity
o 100s of patients; weeks to months
o “proof of concept”
Phase III: long-term safety and tolerability; clinical efficacy
o 1000s of patients; years
o “proof of effectiveness” – convince FDA that drug’s ready for market
o Very expensive phase – imaging, testing monitoring
Phase IV: post-marketing surveillance; develop new indications
o study special pt populations, “real-world” effectiveness
o 1000s of patients; often retrospective
Orphan drugs: intended for conditions affecting <200,000 people (get a little break on some regulations)
IND: Investigational New Drugs: application required for investigational new drugs or approved drugs if:
Change in drug label (package insert: the only info anywhere that’s FDA approved)
Significant advertising changes
8
New route of administration, formulation, dose, pt. population with increase in risk
IRB asks for it
New Drug Application: data submitted to support marketing approval of investigational new drug
Reviewed by advisory committee who make recommendation (approve / disapprove)
FDA not obliged to follow advisory committee recommendations
9
Complementary & alternative medicines
CAMs are important. 11.2% of all out-of-pocket spending in US, 38% of pts use CAMs
Healing is belief based and science based. Whereas scientific medicine is evidence based & changing,
traditional medicine is belief-based, anecdotal, static, and authoritarian. Science = good, other stuff = bad.
1994: Dietary supplement health and education act (DSHEA) effectively neutered FDA (health food lobby won
out; FDA has very little control)
CAM development circumvents the 8-10 year, $1B drug development process: but at the cost of safety/toxicity
studies, effectiveness proven, standardization of the product
Example: PC-SPES (for prostate cancer – even in NEJM) but turned out to have synthetic drugs (hoax)
Herbal medicines generally not standardized (so you can’t study them well or refute claims). Many are
adulterated or inconsistent with their labeling.
Ethically need to be able to know what you’re giving patients.
Scientifically need to be able to replicate a study.
NEEDS TO BE EFFECTIVE & ACCEPTABLY SAFE
Only one herbal medicine has been approved (veregen for topical tx of genital & perianal warts in
immunosuppressed patients) – and even that doesn’t have great results
Several others (witch hazel = cuts & scrapes, senna & psyillum = laxatives) have been approved for modest value
in some illnesses.
10
Molecular Imaging
Molecular imaging: the remote sensing of cellular processes at the molecular level in vivo
(people or lab animals)
Allows early detection of changes in tissue; manage changes in real time for patient (personalized
medicine), facilitates drug development (where is drug going?)
Modalities:
Keys: spatial resolution of techniques, sensitivity (what quantities can be measured – e.g. optical =
picomolar, MRI = micromolar), specificity of probe (just hit target, not normal tissue)
Can be combined with anatomic techniques like CT
Four modalities: Optical, Nuclear (radiopharmaceutical), Magnetic Resonance (MR), or Ultrasound
Nuclear imaging:
PET (Positron emission tomography) – currently the most clinically translatable modality
o More expensive; requires cyclotron, quantitative, 4mm resolution
o Physiologic tracers (15O, 13N, 11C, 18F, 124I)
o Combine with CT: PET-CT to see anatomy
o Receptor/enzyme/transporter mapping; assess metabolism; calculate drug receptor occupancy;
monitor biomarkers for therapy & patient selection for treatments
SPECT (Single photo emission computed tomography)
o Less expensive ($500k), qualitative, 1.5cm resolution
o Uses chelation chemistry
o Example: image for prostate-specific membrane antigen (PSMA) for prostate cancer (if present
outside of prostate, could be recurrance of cancer
Tracer principle: use concentrations of a probe that are so low that they won’t alter the physiology of the
system under study (no pharmacological effect). Makes use in humans more easily approved. Especially good
for radiopharmaceuticals.
Receptor pre-blockade: saturate the target sites with a normal nonlabeled ligand, then apply your probe /
imaging agent. If there’s any signal detected, that shows non-specific / background signal (should only be
binding to your site of interest). Shows specificity. Could also use knockout animals
Signal amplification: enzymatic reporters can be useful because they amplify the signal (your probe, for
instance) – keep working inside the cell (especially good for less sensitive modalities like MR)
Example: C. novyi (anaerobic, goes to anoxic center of tumor). How to image bacteria as they home in? image
with 125I (FIAU) – the toxin produced by a bacterial kinase . Turned out to be toxic (5 deaths) so not a Tx now.
Can also image breast cancer using PET (18F-fluorothymididine = FLT-PET) to detect early cancers.
11
Pharmacokinetics
Pharmacodynamics: what the drug does to the body (deciding on the target) – effect vs. concentration
Pharmacokinetics: what the body does to the drug (hitting the target) – concentration vs. time
What we’re really interested in: PK/PD interrelationship (effect vs. time)
Movement across membranes depends on various factors (size, dynamic polarity, water:octanol distribution,
protein binding, pKa, membrane transporters). Needs to be uncharged to get across (low dynamic polar
surface area < 140 angstoms, lower for brain/blood barrier)
Absorption determinants:
Passive movement: middle ground for hydrophobicity is best to move between compartments
Protein binding: generally only unbound drug can move across membranes
Efficiency issue: high binding is not failure (if approved, it has effect)
Albumin & α-acid glycoprotein are major proteins
Varies with time (↑ α-a-g with inflammation, ↓ albumin with cirrhosis & nephrotic syndrome) so can
change concentrations of highly bound drugs
Affinity can also change (uremia in renal failure decreases binding)
Displacement theoretically possible but no known drug-drug examples
Henderson-Hasselbach Equation
pH = pKa + log(A-/HA); pH = pKa when HA = A-
Acid uncharged when pH < pKa (HA+)
Base uncharged when pH > pKa (HA)
Disease conditions (alkalosis or acidosis) can change how drug moves across membrane
o Gastric fluid 1.5-7, urine 4.5-7.5, blood etc. 7.4. Some drugs can be trapped depending on pH
o pH can change with other drugs (e.g. gastric fluid pH & omeprazole)
Basic definitions
F: Bioavailability (unitless): fraction reaching systemic circulation. Limited by failure to enter solution, short
exposure to absorptive surface, failure to pass across membrane, pre-systemic metabolism so less than 1 in
almost all circumstances.
𝑨𝑼𝑪
Bioavailability= 𝑨𝑼𝑪𝑬𝑽 (where EV = after extravascular dose, IV = after intravascular dose)
𝑰𝑽
EV peaks later, around longer than IV
Low bioavailability affects ability to dose po (may need frequent doses or IV) & can be a feasibility issue
F<1.0 because drugs fail to enter solution, have short exposure to absorptive surface, limited passage
across membranes, and/or or pre-systemic metabolism
Adjust for F when logically required
12
S: Salt (unitless): some drugs are composed of other stuff by weight too
𝒂𝒎𝒐𝒖𝒏𝒕 𝒂𝒄𝒕𝒊𝒗𝒆 𝒅𝒓𝒖𝒈 𝒊𝒏 𝒂𝒅𝒎𝒊𝒏𝒊𝒔𝒕𝒆𝒓𝒆𝒅 𝒇𝒐𝒓𝒎
𝑺 = 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒕𝒐𝒕𝒂𝒍 𝒅𝒓𝒖𝒈 𝒔𝒂𝒍𝒕 𝒊𝒏 𝒂𝒅𝒎𝒊𝒏𝒊𝒔𝒕𝒆𝒓𝒆𝒅 𝒇𝒐𝒓𝒎
Analogous to F
E.g. aminophylline is 80% theophyilline by weight
Vd: Volume of distribution (L): Volume into which dose appears to be uniformly distributed
𝑫𝒐𝒔𝒆
𝑽
= 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏
𝒅
Affected by drug movement across membrane (less movement = higher conc in central compartment)
Use population Vd (adjust for weight – given in L/kg) as first estimate. Can be “lean weight” if not fat
soluble
Generally a theoretical concept: measuring only total, not free drug; only sampling central compartment
ke: Elimination rate constant (1/time): fraction of drug eliminated in a unit of time
Not the elimination rate
First order (not saturated) – constant value (constant fraction eliminated); goes down as saturation
occurs (zero order – constant amount eliminated)
𝑪𝒕 = 𝑪𝟎 𝒆−𝒌𝒕 for elimination
Plot ln(Concentration) vs. Time and your slope is –k
Can backwards-extrapolate to get C0, your initial concentration
𝒌 = 𝑪𝒍/𝑽𝒅
t1/2 : half life (time): how long it takes concentration to drop by half.
Only works for first order.
When Ct/C0 = ½ , equation above simplifies
𝟎.𝟕
o 𝒕 =𝒌
𝟏/𝟐
Another way to look at it
𝟏
o 𝒆−𝒌𝒕 = 𝒏
𝟐
o n = number of half lives elapsed post dose, or number of half lives in dosing interval to find
trough.
Or:
𝟏 𝒏
o 𝑪𝒕 = 𝑪𝟎
𝟐
13
Rac: Rate of accumulation
𝐶𝑚𝑎𝑥 ,𝑠𝑠 1 1
𝑅𝑎𝑐 = 𝐶 = 1−𝑒 −𝑘𝜏 = 1
𝑚𝑎𝑥 ,1𝑠𝑡 𝑑𝑜𝑠𝑒 1− 𝑛
2
If you’re dosing a drug with a long half life and dosing, say, every 1/5 half life, you can get a big variation
over time. If you’re dosing ever 4-5 half-lives, you don’t get much buildup
If you give a loading dose & follow up with continuous infusion, the curves sum to be almost square (infusion
accumulates as loading dose decays.
Concentration-constrained dosing: how to calculate dose & interval for peak & trough
Shortcut: if you want Cmax / Cmin to be 2, max interval is t(1/2). If you want 4, 2t(1/2) is your interval
Interval (Rate = ratio) – Cmax/Cmin = 2n
𝐶 𝑚𝑎𝑥 ,𝑠𝑠
ln
𝐶 𝑚𝑖𝑛 ,𝑠𝑠
o 𝜏𝑚𝑎𝑥 = where 𝑘 = 0.7/𝑡1
𝑘 2
Dose=Difference
o Single loading dose (get up to the max SS)
o 𝐷 = 𝐶𝑚𝑎𝑥 ,𝑠𝑠 − 𝐶𝑝𝑟𝑒𝑠𝑒𝑛𝑡 ∗ 𝑉𝑑
o Correct for F, S when needed
Intermittent maintenance dose (given every 𝜏𝑚𝑎𝑥 )
14
o 𝐷 = 𝐶𝑚𝑎𝑥 ,𝑠𝑠 − 𝐶𝑝𝑟𝑒𝑠𝑒𝑛𝑡 ∗ 𝑉𝑑
o Correct for F, S when needed
Ka (absorption rate constant) – if a lower Ka, then slower abosorption. Peak is lower, trough is higher, and AUC
is the same. Peak is also later.
Slower absorption can be good – keeps a narrow window in your peaks and troughs (e.g. extravascular
dosing)
Renal clearance: can adjust for creatinine clearance if drug is cleared by the kidney (age, weight, gender taken
into account). If creatinine clearance is lower, you can drop your infusion to get to the same steady state
concentration (but it will take longer! T1/2 is larger)
15
Autonomic Pharmacology I - Parasympathetic
Basics:
Nervous system: afferent (sensory information), integration in ganglia in CNS structure, efferent
(somatic motor = voluntary skeletal mm, autonomic – involuntary smooth mm), mostly antagonistic
Parasympathetc = homeostasis, sympathetic = fight or flight
PNS Actions:
Homeostasis, opposes sympathetic activity generally
Constricts smooth muscle, increases glandular secretions usually
Classical actions: pupil constriction, bronchial constriction, decreased heart rate, relax sphincters &
contract GI segmental/longitudinal mm, contract bladder (relax sphincter)
Cholinergic synapse:
AcH synthesized by choline acetyltransferase
Ca+ dependent release (+ B-bungarotoxin, black widow venom, - botulism toxin by cleaving SNARE)
Muscarinic AcH receptor (+pilocarpine, - atropine)
o 7-membrane-spanning GPCR
o M1-M5 subtypes with selective tissue expression, specific functions but overlap
o M2 is cardiac-selective; subtyping hasn’t really been exploited clinically so far
Acetylcholinesterase breaks it down (- neostigmine, soman)
o This is the turnoff (compare to sympathetic)
o Neuronal AchE and also serum/liver (butrylcholinesterase) so you can’t just inject Ach into gut
Choline uptake
MUSCARINIC AGONISTS
16
metoclopramide Mechanism of Action: Muscarinic AcH receptor agonist
Effects: increases gastric emptying; anti-emetic (dopamine receptor agonist), also enhances cholinergic
effects
Indications: First-line gastroparesis & anti-emetic agent
Administration: oral
Other: a.k.a. "Reglan"
MUSCARINIC ANTAGONISTS
ACETYLCHOLINESTERASE INHIBITORS
May be therapeutics (physostigmine for glaucoma), antidotes to poisons (pyridostigmine), or toxins
themselves (sarin) depending on their affinity for AchE, route of administration, dose, etc.
Many insecticides, nerve gases, etc. fall in this category
AchE is a serine protease that cleaves Ach to acetate & choline in synaptic cleft
Found in high molecular weight aggregates (stable = low turnover = really bad if you mess it up)
17
pralidoxime Mechanism of Action: nucleophilic attack on AchE-sarin covalent complex
Effects: Reversal of sarin AchE poisoning
Indications: sarin AchE poisoning
Other: used along with atropine for sarin & other similar AchE poisons
18
Autonomic Pharmacology II - Sympathetic
Anatomy:
From thoracolumbar spinal cord; ganglia are paraverterbral & longer post-synaptic fibers
Ganglionic receptors: nicotinic cholinergic
Target receptors: adrenergic
Primary postganglionic neurotransmitter: norepinephrine
Adrenal medulla is like a big postganglionic neuron, releases epinephrine
Stimulation results in a widespread reaction
Physiology:
“Fight or flight”response
Smooth mm: relax or constrict
Classical actions: dilate bronchi, ↑glucose from liver, ↑rate & stroke volume from heart (↑ cardiac
output), ↑blood flow to skeletal mm, ↓motility & ↑ sphincter tone in gut
Activation via enervation of target and adrenaline (=epinephrine) in blood circulation from adrenals
Adrenergic synapses
NE synthesized in neuron (tyrDOPA dopamineNE). Epinephrine synthesized in adrenal gland
Tyrosine hydroxylase is the rate-limiting step of synthesis & activated by sympathetic stim.
o α-methyltyrosine blocks tyrosine hydroxylase, used in management of pheochromocytoma
(usually benign tumor of adrenal that fires out too much catecholamine)
Release of NE is Ca-dependent
o Some agents can act as false neurotransmitters, replacing NE in secreted vesicle & ↓NE effect
o Tyramine, amphetamine, ephedrine: sympathomimetic (enhance NE secretion)
Adrenergic receptor (many agonists & antagonists) on post-synaptic side
o GPCR
NE transporter brings NE back into pre-synaptic neuron (blocked by tricyclic antidepressants)
o Turnoff mechanism is re-uptake (not breakdown like parasympathetic)
Monoamine oxidase breaks down NE & deaminated products extruded (target of antidepressants)
Adrenal glands have PNMT which converts NE (noradrenaline) to ephinephrine (adrenaline), major adrenal
medulla hormone. NE and ephinephrine have different pharmacological effects
α-receptor pharmacology
Non-selective α-receptor agonists: epinephrine, NE, phenylephrine, dopamine (see end of section)
Non-selective α-receptor antagonists:
19
phenoxybenzamine Mechanism of Action: nonselective antagonist of α adrenergic receptors
Effects: Reduces NE effect via inhibition
Indications: pheochromocytoma: adrenal tumor producing large amounts of
catecholamines (tumor usually benign; reverse effects)
α1-receptor agonists:
phenylephrine Mechanism of Action: selective agonist of the α1 adrenergic receptor
Effects: induces vasoconstriction
Indications: hypotension, nasal congestion
Administration: po or nasal spray as decongestant
α1-receptor antagonists:
prazosin Mechanism of Action: selective antagonist of the α1 adrenergic receptor
Effects: blocks smooth muscle constriction (relaxes ureters); vasodilation (can help with
hypertension)
Indications: enhances urine flow in benign prostatic hyperplasia, especially with hypertension
α2-receptor agonists:
clonidine Mechanism of Action: selective agonist of the α2 adrenergic receptor.
Effects: decreases NE release pre-synaptically (α2 is on pre-synaptic side, for feedback inhibition).
Indications: hypertension (reduces blood pressure), used for withdrawal in substance abuse
Administration: orally (both indications) or patch (substance abuse)
β -receptor pharmacology
Non-specific β receptor agonists:
isoproterenol Mechanism of Action: nonselective agonist of the ß adrenergic receptors
Effects: stimulates cardiac output, dilates bronchial smooth muscle, dilates vascular smooth
muscle
Indications: bradychardia or heart block; rarely used to treat asthma
β1 receptor agonists:
20
dobutamine Mechanism of Action: selective agonist of ß1 adrenergic receptor
Effects: increases cardiac rate & force of contraction (increased cardiac output); dilates
coronary arteries to reduce afterload
Indications: cardiomyopathy with CHF, especially in anginal states
Administration: IV
Other: doesn't work indefinitely
β1 receptor antagonists:
metoprolol Mechanism of Action: selective antagonist of ß1 adrenergic receptor (beta-blocker)
Effects: reduces cardiac output, reducing demand on heart
Indications: hypertension & angina
Other: also may promote better filling of coronary arteries by increasing length of diastolic phase
β2 receptor agonists:
albuterol Mechanism of Action: selective agonist of ß2 adrenergic receptor
Effects: dilates bronchial smooth muscle & uterine smooth muscle
Indications: asthma; stopping premature labor
Other: very few cardiac side effects because of ß2 selectivity. Also promotes glycogenolysis in liver
(be careful not to precipitate diabetic state)
dopamine Mechanism of Action: Acts on D1 receptor in vasculature; also α and ß in high doses
Effects: Pressor (increases blood pressure), used in cardiac situations.
Indications: Low dose (renal dose) can be used to impact D1 receptor only if patient has low renal
perfusion; higher doses impact D, α, and ß receptors and is first pressor in most instances of
shock (low BP)
Misc: Adenosine receptor pharmacology: treating asthma, for example, by antagonizing adenosine at airways;
Nitric oxide signaling is also autonomic.
21
SUMMARY TABLE (autonomic I and II)
22
An Overview of Cancer Chemotherapy
Local treatments
Surgery (solid organ malignancy; need systemic disease, need staging before surgery to determine extent)
Radiation therapy (localized cancers that can’t be removed surgery; also as adjuvant with surgery &
palliation of metastases that can cause morbidity)
Chemotherapy (sometimes given regionally – e.g. hepatic artery for colonic cancer liver metasteses)
Other (immunotherapies, etc. – often experimental)
Cancers vary in responsiveness to
Systemic treatments cytotoxic chemotherapy
Hormone / Growth Factor (remove / antagonize trophic
hormones, e.g. estrogen for breast cancer, androgens for Highly responsive (Hodgkin’s, Wilm’s
prostate cancer) tumor)
o Tamoxifen (anti-estrogen) – adjuvant after resection of Responsive (acute leukemia in
breast cancer or systemic for metastatic children, retinoblastoma, testicular
Chemotherapy: for systemic cancers, for cure (leukemia, testis, cancer)
lymphoma) or pallation (solid organ cancers) Moderately responsive (acute
o Can be used as adjuvant to improve local treatment leukemia in adults, multiple myeloma,
potential breast cancer, prostate, ovarian)
Other (immunotherapy, gene therapy, etc.) Partially responsive (glioblastoma,
colorectal, pancreatic islet cell
Treatments can target: carcinoma, bladder)
Minimally responsive: (liver,
Targets unique to cancer cells (mutant gene products,
pancreatic cancer; melanoma)
oncogenic virus products)
Qualitative/quantitative differences in cancer cells (cell cycle
effectors, macromolecules, biosynthetic enzymes, signal transduction pathway components) that are also
present in normal cells
o Therapeutic index (LD50/ED50)usually low for anti-cancer drugs (bad) because of this
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Fractional cell kill: a specific dose of chemotherapeutic drug kills a specific fraction of tumor cells regardless
of tumor cell population (see logarithmic decline with therapy)
Norton-Simon hypothesis
Based on observation that improvements in response rates from
chemotherapy doesn’t lead to improvements in survival
General idea: a more effective treatment will kill lots of cells, get
down to the exponential growth part of the curve; cancer cells
replicate quickly and “catch up” to a similar less-effective
treatment. Mortality occurs way out in plateau phase.
Goldie-Coldman hypothesis
Luria and Delbruck: in bacteria, rate of genetic variants appearing related to rate of cell division &
probability of variant arising with each division (genetic instability)
Goldie / Coldman: considered in cancer cells & anti-neoplastic drof genetic instability in population
o Although rate of appearance is independent of total number, absolute number of subclones is
greater for a greater size of cancer cell population (need to detect early!)
Experiment (L-D Fluctuation Analysis): culture cells and then:
o Plate concentration of mixture of cultured cells on a bunch of plates: about the same amount of
resistance occurs in each plate (Poisson distribution = random)
o Pick out individual cells, grow up clonal population, and plate same concentration. Non-Poisson
distribution in amount of resistance on each plate (mutation can occur early or late in clonal
growth process)
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So: cancer might respond well but eventually these subclones can emerge and treatment fails.
Rationale for combination chemotherapy, combined modality treatments, debulking surgery: rapidly reduce
the total # cancer cells and absolute # drug-resistant subclones
Why are some cancers readily curable & others poorly responsive?
1. Cancer cell kinetic properties. Curable cancers may have more rapid growth (antineoplastic drugs kill
them better).
2. Cancer cell biochemical properties. Noncurable cancers can detoxify, extrude, or otherwise escape
antineoplastic drugs.
3. Cancer cell phenotypic properties. Related to cells of origin of cancer (not well defined) – e.g. testis
cancer more responsive than prostate.
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Principles of antibody therapy for cancer
Antibody clearance:
Abs are too big to go through glomeruli (except in renal disease)
Fab fragments are small and are therefore cleared within hours
Chimeric Ab have mouse variabble region, human constant region
Humanized Ab have partially human variable regions too
Lymphoma:
Ron Levy:
o B-cells display “idiotype” (specific B-cell receptor expressed on surface)
o Use the clonal nature of B-cell lymphomas (same idiotype) as target
o Follicular lymphoma: slow growing, could wait for treatment, expected to live several years, IgG
on cell membrane
o Made IgG for each pt’s lymphoma in lab and treated them (1st patient was big success, mixed
results afterwards)
o Serum sickness: immune reaction against foreign antigens
o One problem: Human Anti-Mouse Antibody (HAMA) – retreatment difficult (already have
HAMA)
o Recurrence: anti-idiotype ab no longer bound to tumor cells (somatic hypermutation in B-cells
& in this lymphoma = development of new lymphocytes)
o Precise but time consuming & recurrence possible
CD20 & Rituximab
o CD20 only expressed on B cells (not plasma cells, not precursor stem cells)
Lets you regenerate your B cells after treatment
o When anti-CD20 Ab bind, no internalization of complex & Cd20 not downregulated
Rituximab
Toxicity: More adverse events in first infusion (killing most B-cells at first) – opposite of other Ab
therapies, where serum sickness sets in more with more immune reaction to foreign Abs. Due to large
number of dead B-cells.
THINGS TO KNOW:
o HAMA don’t develop because rituximab is killing B cells, which would generate the human anti-
mouse antibodies
o Serum IgG levels don’t fall because plasma cells make most of the IgG in serum. No CD20
means they’re not killed
o Why do B cells recover? Hematopoetic stem cells don’t have CD20 so aren’t killed.
Efficacy of rituximab depends on CD20 expression; often used with other therapies
Mechanisms of Action:
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o Directly induces apoptosis (lymphocytes’ own self-destruct mechanism triggered by CD20
binding)
o Antibody dependent cell-mediated cytotoxicity (ADCC) – killed by NK cells & others
o Complement fixed & cells lysed.
Reistance
o CD20 not downregulated & escape mutations are rare
o Major mechanisms:
1. Failure to generate ADCC (genetic variant in Fc binding receptor)
2. Variations in apoptotic pathways (probably most common)
o Overall: Ab still binds to tumor, just doesn’t kill it
Treatment considerations:
o Everyone eventually relapses
o Maintenance therapy?
1. inhibits ability to generate new IgG
2. ↑ susceptibility to certain infections
o Retreatment generally works if pts have not received rituximab recently (but not if on
maintence)
Nomenclature
Antibody conjugates Ri-tu-xi-mab; 1-2-3-4
Radioimmunoconjugates 1. Anything
o Murine Ab; target CD20 and conjugated to 2. tu(m) = tumor is target
radioactive isotopes 3. type of antibody
o Crossfire increases action (overcomes resistance) a. o = mouse
because neighboring cells are killed too by b. xi = chimeric
radiation (those which are apoptosis-resistant) c. zu = humanized
4. mab = monoclonal antibody
Immunotoxins work by a similar idea
If tumor is radiosensitive, conjugate radioactivity; if not,
conjugate a toxin (but toxin may be antigenic, preventing
Half-lives
retreatment
Fab = hours
Consequences of Ab therapy Mouse = days
Targets Chimera = days to weeks
o Looking for muntant proteins, only in cancer, etc. Human = months
– but now maybe some tissues (e.g. b-cells) are
disposable? Thyroid / prostate?
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Mechanisms and uses of antimetabolite drugs, signal transduction inhibitors, and anti-
angiogenesis drugs in antineoplastic therapy
General notes:
Antimetabolites: In the end, these pretty much all work by leading to DNA double-strand breaks
(↓nucleotide pool or ↓DNA polymerase speed; causing DNApol to get stuck & cause DBS without
repair)
o All pretty much have bone marrow toxicity
In traditional treatment, all roads lead to DNA (now more of a targeted approach
Antimetabolites:
Mimic structure of normal metabolic species; inhibit enzymes in both normal and tumor cells
Administered as prodrugs that require metabolic activation
Inhibit deoxynucleotide and DNA synthesis; kill cells in S phase
Targeting tumor cells: take advantage of different transport or enzymatic activation of prodrug, or of
cells that are progressing through cell cycle
Nonneoplastic cells most affected: rapid cell division
o Hair follicle, bone marrow, intestinal epithelium cells
o Therapy induced leukemia is major complication
Limitations: drug delivery (central hypoxic zone of solid tumors), not all tumor cells are cycling, fixed
percentage killed with each treatment, need active immune system, drug resistance common
Folate antagonists:
Inhibit dihydrofolate reductase (DHFR) which reduces folic acid to dihydrofolate (DHF) and
tetrahydrofolate (THF)
THF is required to carry methyl & methylene (1-C) groups for thymidine and purine biosynthesis
methotrexate Mechanism of Action: Folic antagonist (antimetabolite). Inhibits dihydrofolate reductase (DHFR).
Effects: Inhibits DHFR which is involved in synthesis of THF from folic acid. THF is the methyl/methelyne
carrier for purine and thymidine synthesis.
Indications: wide variety of cancer breast cancer, colorectal cancer, lymphoma
Administration: often paired with leucovorin shortly after MTX given ("leucovorin rescue") - replentishes
folate stores
Toxicity: mucositis, kidney damage, hepatotoxicity
Resistance: Reduced uptake; reduction in enzymes that add polyglutamate; DHFR gene amplification
Other: Actively transported into cells. Requires activation by addition of several glutamates (traps in cell;
enhances inhibition). Aka MTX
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hydroxyurea Mechanism of Action: Inhibits ribonucleotide reductase. Antimetabolite antineoplastic agent.
Effects: Ribonucleotide reductase reduces NDPs to dNDPs for DNA synthesis
Indications: Leukemias; head and neck cancers
Toxicity: Standard (bone marrow, etc.)
Resistance: Overexpression of reductase
Note: Nucleoside analogs (5-FU, 6-percaptopurine, 6-thioguanine, etc.) are able to be transported into cell via
nucleoside transporter, and are then p-lated and trapped in cell. They must fit into a kinase in the cell, however
(resistance mechanism)
5-fluorouracil Mechanism of Action: Covalently modifies thymidylate synthase, the enzyme which converts dUMP to
TMP. Triphosphate form can also be incorporated into DNA and cause strand breaks
Effects: Antimetabolite antineoplastic agent.
Indications: Colorectal and breast cancer
Administration: IV and oral. Often co-administered with leucovorin. TS uses folate as a cofactor (also when
5-FU binding), so adding a folate analog like leucovorin pushese the inhibitory equilibrium through
(LeChatlier's). Also often co-administered with 5-ethynyluracil, which inhibits dihydropyrimidine
dehydrogenase in intestine.
Toxicity: Bone marrow suppression
Resistance: Decreased activity of activating enzyme. Intestinal enzyme dihydropyrimidine dehydrogenase
can inactivate by converting it to dihydroform and preventing absorption.
Other: Transported in via nucleoside transporter, then P-lated and trapped in cell (needs to fit in kinase)
6-mercaptopurine, Mechanism of Action: Competitive inhibitor of several enzymes in purine synthesis pathways (looks
6-thioguanine, like guanine); also gets incorporated into DNA
azathioprine Effects: Purine biosynthesis antagonist; antimetabolite antineoplastic agent.
Indications: leukemias
Administration: oral
Toxicity: Bone marrow suppression
Resistance: inactivated by xanthine oxidase (XO). Decrease in HGPRTase activity is common resistance
mechanism.
Other: Must undergo activation to form mononucleotide (add sugar) via HGPRTase. Also inactivation,
elimination in urine pathways competing.
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gemcitabine (2', 2' difluorodeoxycitidine) Mechanism of Action: Inhibits DNA polymerase by blocking DNA strand
elongation (substrate but can't elongage afterwards)
cytosine arabinoside (cytarabine, Ara-C.) Effects: Antimetabolite antineoplastic agent
Indications: pancreatic cancer (gemcitabine), chronic lymphocytic leukemia
fludarabine (arabinosyl-2-fluoroadenine) (CLL – fludarabine), acute myelogenous leukemia (AML – cytosine
arabinoside)
5-azacytidine (5-aza-C) Toxicity: myelosuppression
Resistance: decreased activity of activating enzymes; decreased nucleoside
2-chlorodeoxyadenosine (cladribine, 2-CdA) transport across cell membrane
Other: Must be activated by deoxycytidylate kinase and nucleoside
diphosphate kinase
Resistance to all of these is via amplifaction of oncogenic protein kinase gene, resistance mutations in kinase
catalytic domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)
imatinib Mechanism of Action: inhibits tyrosine kinases (BCR-ABL, c-KIT, PGDF receptor kinase)
Effects: Tyrosine kinase inhibitor; antineoplastic agent. BCR-ABL is a hyperactive fusion kinase implicated in
CML (philadelphia chromosome). PGDF RK = platelet-derived growth factor receptor kinase
Indications:CML, gastrointestinal stromal cancer.
Resistance: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain.
Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)
Other: aka Gleevec. BCR-ABL + cells are resistant to apoptosis, proliferate more, and have altered adhesion
properties.
trastuzumab Mechanism of Action: monoclonal antibody that binds to extracellular region of HER2, a
transmembrane receptor tyrosine kinase from epidermal growth factor receptor family
Indications: Antineoplastic agent. Breast cancer (25% invasive primary breast cancers have HER2
overexpression)
Resistance: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic
domain. Second-generation protein kinase inhibitors have bene developed (active against mutant
PKs)Resistance:
Other: a.k.a. Herceptin
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cetuximab Mechanism of Action: monoclonal antibody against epidermal growth factor receptor (EGFR).
Indications: Antineoplastic agent. Epithelial tumors (colorectal cancer, head and neck tumors)
Resistance: amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic
domain. Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)
gefitinib Mechanism of Action: Tyrosine kinase inhibitor (inhibits epithelial growth factor receptor kinase)
Indications: Non-small-cell lung cancer (NSCLC)
Resistance:amplifaction of oncogenic protein kinase gene, resistance mutations in kinase catalytic domain.
Second-generation protein kinase inhibitors have bene developed (active against mutant PKs)
Other: Higher response if EGFR mutated or overexpressed.
Basic idea: formation of new blood vessels essential for tumor progression.
Protease inhibitors block ECM breakdown
Inhibitors of endothelial cell proliferation (small molecule receptor protein kinase inhibitors like
Gleevec & endogenous peptides)
Proteosome inhibition
Basic idea:
NF-kappa-B controls expression of stress response genes & others that promote cell survival
I-kappa-B inhibits NF-kappa-B, degraded in proteosome after ubiquination to activate NF-kappa-B
Less proteosome activity = more NF-kappa-B inhibition
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Cancer Chemoprevention
As many as 80% cancers in men, 77% in women can be prevented – idea is to detect early for public health
intervention before clinical appearance. For instance, Japanese migrants to US assume US-type cancer risk
profile, and their sons even more so (even without genetic mixing).
Tobacco and diet are the big risks (30%, 35% cancer deaths attributable respectively)
Can be synergistic interactions between risk factors (e.g. alcohol & tobacco use in squamous carcinoma of
esophagus – 150x higher risk if heavy use of both)
Cancer chemoprevention: the use of natural or synthetic agents that retard, block, or reverse carcinogenesis
before invasive malignancy develops. (chemotherapy is for those who already have cancer)
To determine preventive measure, need to consider cancer risk, treatment risk, and treatment benefit: low risk
requires low intervention like lifestyle modification, high risk can require high-level intervention like surgery.
Medium-high risk might require chemoprevention.
Estrogen has good and bad effects (improves cognition, lowers cholesterol, prevents bone loss… but also
increases breast / endometrial cancer & thromboembolism risk).
Tamoxifen and raloxifene are two examples of SERMS – can act like estrogen in some tissues and antagonize
estrogen in others
Idea: reduce androgen activity. There are a bunch of inihibitors of all steps of androgen synthesis.
In some prostate cancers, oncogene translocated behind androgen-based promoter.
Finasteride and duasteride approved for male pattern baldness, BPH (PC chemoprevention)
Two big trials (PCPT & REDUCE): big prevalence of prostate cancer already; couldn’t use PSA because
PSA production related to androgens so had to use biopsy
Outcomes: both saw reduction in prostate cancer, but one showed increase in high grade cancer.
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Random area biopsy – maybe shrinking prostate with inhibitors increased chance that high grade cancer
would be found?
Basic idea: arachidonic acid, inflammation might be part of adenoma cancer recurrence in colorectal cancer.
Wanted to use COX-2 inihbitors like celecoxib (Celebrex) and rofexocib (Vioxx) to selectively inhibit COX-2
(NSAIDs, originally for arthritis). COX-2 makes prostaglandins around epithelial cells of GI tract.
More stuff:
Cruciferous vegetables might help cancer chemoprevention: sulforaphane
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Antineoplastic alkylating agents and platinum compounds
Akylating agents react with certain nucleophilic areas in DNA (e.g. N7 of guanine) with several consequences:
Mispairing of modified base
Crosslinking of DNA bases on same strand (intrastrand) or opposite strands (interstrand)
Crosslinking DNA to proteins, RNA, other macromolecules
DNA strand scission (weaken sugar-phosphate backbone; endonucleases attack during repair attempt)
2. Substituted nitrogen mustards (melphalan & chlorambucil) which are less reactive & can be given po.
melphalan, Mechanism of Action: Bifunctional alkylating agent; antineoplastic agent.
chlorambucil Effects: Forms interstrand or intrastrand DNA cross-links. Can also cross-link DNA to other macromolecules,
cause DNA strand scission, or mispairing of modified base
Indications: multiple myeloma (mephlan), chronic lymphocytic leukemia (CLL), indolent lymphomas,
Waldenstrom's macroglobulinemia (chlorambucil)
Administration: can give PO
Toxicity: bone marrow suppression, amenorrhea, sterility
Other: substituted nitrogen mustard; less reactive than mechlorethamine
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cyclophosphamide, Mechanism of Action: Bifunctional alkylating agent
ifosfamide Effects: Must first undergo metabolic activation (P450). Forms interstrand or intrastrand DNA cross-
links. Can also cross-link DNA to other macromolecules, cause DNA strand scission, or mispairing of
modified base.
Indications: Cyclophosphamide: Many human cancers (non-Hodgkin's lymphoma, breast cancer).
Can also be used with bone marrow or peripheral hematopoietic stem cell transplantation therapy
(high-dose). Used to treat auto-immune diseases as well. Ifosfamide: sarcomas & many other cancers
Administration: Administering with 2-mecaptoethane sulfonate and vigorous hydration can help
prevent cystitis
Toxicity: bone marrow suppression, alopecia, gonadal toxicity, and hemorrhagic cystitis (diffuse
inflammation of the bladder leading to dysuria, hematuria, and hemorrhage) resulting from excretion
of a reactive metabolite (acrolein). Ifosfamide has more hemorrhagic cystitis, less bone marrow
suppression than cyclophosphamide
Other: Most commonly used alkylating agent. Stem cells have aldehyde dehydrogenase, which
protects from the active form of cyclophosphamide (which means they won't get killed)
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Mechanisms of resistance to antineoplastic drugs generally fall under two categories:
1. Chemical detoxification. E.g. glutathione, glutathione-S-transferases, etc. Resistance usually comes
from this pathway (think phase II enzymes, etc. – could be upregulated, for instance)
2. DNA repair. Less common – excision repair, mismatch repair, etc.
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depth, just less broad)
o Transfusion of RBC or platelets can sometimes be used
Gonadal dysfunction
o Lots of ongoing mitosis/meiosis & proliferation in this area
o Testes > ovarian follicles for dysfunction (ongoing spermatogenesis vs arrested ova)
o Important factors:
Age/gender (pubertal gonads resistant; women < men for dysfunction)
Chemo agent & dose (alkylating agents & platinum compounds especially bad
Make sure to bank sperm / store eggs if possible!
Some regimens have huge differences in recovery rates
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Additional drugs (maybe know?) Under “other” (alkylating agents?)
Nitrosureas
Carmustine: lipophilic; treat brain tumors (drug-implanted wafer: glioblastoma multiforme)
o (toxicities: bone marrow suppression, nausea & vomiting)
Streptozotocin: antibiotic that is retained in beta-islet cells of pancreas; treats islet cells tumors
o Nephrotoxicity, hepatotoxicity, diabetes
Aziridines
Thiotepa: breast cancer; instill in bladder for superficial bladder cancer
o Usual toxicities
Mitomycin C: antibiotic – limited use in recta / pancreatic cancer; superficial bladder cancer as instillate
o Usual toxicities
o Rare but significant: interstitial pneumonitis, nephrotoxicity, hepatic veno-occlusive disease,
hemolytic-uremic syndrome
Alkane sulfonates
Busulfan: high dose chemo for bone marrow or peripheral hematopoetic stem cell transplants
o Usual toxicities + pulmonary fibrosis, hepatic veno-occlusive disease, skin pigment changes
Methylating agents
Procarbazine: Hodgkin’s disease. Normal toxicities + peripheral neuropathy, sterility, secondary
leukemia
Dacarbazine: Hodgkin’s disease. Normal side effects + “flu-like” syndrome, Budd-Chiari syndrome,
photosensitivity
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DNA Topoisomerase-targeted drugs and mitotic spindle poisons
Many of the other drugs (alkylating agents, etc.) were rationally designed; these are screened natural products
Topoisomerase-targeted drugs
o DNA bending (“indirect block”): bend DNA in a way that puts active site in conformation where
reversal of attack isn’t favorable. E.g. minor groove binding agents (investigational).
Curved structure and positive charges let them fit in to minor groove well
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Increase amount of covalent complex by DNA bending; S-phase specific
Can increase/decrease effects of other topo I poisons
o Actinomycin D
Induces DNA bending / structural pertubations
Precise genomic target not known (maybe RNApol instead of topo I)
actinomycin D Mechanism of Action: "hybrid" minor groove binding antineoplastic agent
Effects: Precise target not known. Probably induces DNA bending / structural pertubations (may target
RNA polymerase instead of topoisomerase I)
Indications: Childhood malignancies (Wilm's tumor, Ewing's sarcoma, embryonal rhabdosarcoma)
Toxicity: Usual (myelosupression, hair loss, oral / GI ulceration)
Resistance: MDR drug efflux pumps (ABC-type)
Epipodophylotoxins (non-intercalative)
etoposide Mechanism of Action: Topoisomerase II-targeted antineoplastic agent.
teniposide Effects: Nonintercalative; increases covalent DNA-enzyme complex by unknown structural mechanism
Indications: Many types of cancers
Toxicity: Usual (myelosuppression, mucositis, nausea, anaphylaxis)
Resistance: MDR drug efflux pumps (ABC-type)
Anthracyclines (intercalative)
doxorubicin Mechanism of Action: Topoisomerase-II-targeted antineoplastic agent.
daunorubicin Effects: Intercalates into & stabilizes DNA-topo II covalent complex by direct or indirect interaction
Indications: solid tumors (doxorubicin); ALL, AML (acute leukemias) (daunorubicin)
Toxicity: Dose-limiting acute & chronic cardiotoxicity. Liver toxicity (where metabolism occurs -
hydrophobic, so bile excretion).
Resistance: MDR drug efflux pumps (ABC-type). Cardiotoxicity from quinone groups (generates hydroxyl
radicals)
Spindle basics:
Made of microtubules (α & β subunits; dynamic structure ; bind GTP & hydrolize to GDP)
Assemble: heterodimers protofilaments microtubules
Important in mitosis (don’t get good DNA segregation without it)
Lots of tubulin in neurons for axonal transport neurologic toxicity of tubulin-binding agents
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Vinca alkaloids
Bind to β-tubulin (as monomer?), which disturbs polymerization & disrupts protofilament structure
vincristine Mechanism of Action: Mitotic spindle poison (antineoplastic agent). Vinca alkaloid
vinblastine Effects: binds to beta-tubulin (distorts protofilament structure / polymerization, slows dynamics, affecting
vinorelbine ability to undergo mitosis)
Indications: ALL, lymphoma, hodgkin's, childhood malignancies (vincristine), germ cell tumors, Hodgkin's
disease (vinblastine), lung, breast cancer (vinorelbine)
Toxicity: liver toxicity, myelosuppression. Vincristine: neurotoxicity (limits dosage)
Resistance:MDR drug efflux pumps (ABC-type)
Taxanes
Bind to β-tubulin, stabilizing lateral tubulin contacts (freezing filaments in place)
paclitaxel Mechanism of Action: Mitotic spindle poison. Taxane.
docetaxel Effects:Binds to beta-tubulin, maybe stabilizing lateral contacts & freezing protofilament in place. Slows down
microtubule dynamics, hurting ability to undergo mitosis.
Indications: ovarian, breast cancers (paclitaxel), metastatic breast cancer (docetaxel)
Toxicity: dose-limiting myelosuppression. Peripheral neuropathy (paclitaxel more effects than docetaxel)
Resistance: MDR drug efflux pumps (ABC-type)
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