Antimicrotubules

1. Antimicrotubule Agents
DR.KIRAN KUMAR BR

2. Microtubules are vital and dynamic cytoskeletal polymers
that play a critical role in cell division, signaling,
vesicle transport, shape, and polarity, which make them
attractive targets in anticancer regimens and drug
design.
Microtubules are composed of 13 linear protofilaments of
polymerized α/β-tubulin heterodimers arranged in
parallel around a cylindrical axis and associated with
regulatory proteins such as microtubule-associated
proteins, tau, and motor proteins kinesin and dynein.
The specific biologic functions of microtubules are due to
their unique polymerization dynamics.

3. Microtubules are primarily recognized as being principal
components of the mitotic spindle apparatus that separates the
duplicate set of chromosomes.
They also play critical roles in many interphase functions such as
maintenance of cell shape and scaffolding, intracellular
transport, secretion, neurotransmission, and possibly the relay
of signals between cell surface receptors and the nucleus .
The specific biologic functions of microtubules are due to their
unique polymerization dynamics.
Tubulin polymerization is mediated by a nucleation-elongation
mechanism. One end of the microtubules, termed the plus end,
is kinetically more dynamic than the other end, termed the
minus end.

4. Microtubule dynamics are governed by two principal
processes driven by guanosine 5′-triphosphate (GTP)
hydrolysis: poleward flux is the net growth at one end of the
microtubule and the net shortening at the opposite end, and
dynamic instability, which is a process in which the
microtubule ends switch spontaneously between states of
slow sustained growth and rapid depolymerization.
Antimicrotubule agents are tubulin-binding drugs that directly
bind tubules, inhibitors of tubulin-associated scaffold
kinases, or inhibitors of their associated mitotic motor
proteins to, ultimately, disrupt microtubule dynamics.
They are broadly classified as microtubule stabilizing or
microtubule destabilizing agents according to their effects
on tubulin polymerization.

6. TAXANES
Taxanes were the first-in-class microtubule stabilizing drugs.
Ancient medicinal attempts at cardiac pharmacotherapy using
material from the toxic coniferous yew tree, Taxus spp., were
likely related to the plant’s alkaloid taxine effect on sodium and
calcium channels.
Taxane compounds are the result of a drug screening of 35,000
plant extracts in 1963 that led to the identification of activity
from the bark extract of the Pacific yew tree, Taxus brevifolia.

7. Paclitaxel was identified as the active constituent with a report of
its activity in carcinoma cell lines in 1971.
Motivation to identify taxanes derived from the more abundant
and available needles of Taxus baccata led to the development
of docetaxel, which is synthesized by the addition of a side
chain to 10-deacetylbaccatin III, an inactive taxane precursor.
The taxane rings of paclitaxel and docetaxel are linked to an ester
side chain attached to the C13 position of the ring, which is
essential for antimicrotubule and antitumor activity.
Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a
formulation that avoids the solvent related side effects of non–
water-soluble paclitaxel and docetaxel.

8. Overcoming docetaxel and paclitaxel’s susceptibility to the P
glycoprotein efflux pump led to the development of Cabazitaxel.
Cabazitaxel is synthesized by adding two methoxy groups to the 10-
deacetylbaccatin III, which results in the inhibition of the 5′-
triphosphate–dependent efflux pump of P-glycoprotein.
Paclitaxel initially received regulatory approval in the United States in
1992 for the treatment of patients with ovarian cancer after failure of
first-line or subsequent chemotherapy.
Subsequently, it has been approved for several other indications,
including advanced breast cancer, combination chemotherapy of
lymph node–positive breast cancer, advanced ovarian
cancer,second- line treatment of AIDS-related Kaposi sarcoma, and
first-line treatment of (NSCLC) in combination with cisplatin .

9. Docetaxel was first approved for use in the United States in 1996 for
patients with metastatic breast cancer that progressed or relapsed
after anthracycline-based chemotherapy, which was later broadened
to a general second-line indication.
Subsequently, it received regulatory approval in adjuvant
chemotherapy of stage II breast cancer in combination with
Adriamycin and cyclophosphamide (TAC), and first-line treatment
for locally advanced or metastatic breast cancer.
In addition, docetaxel has indications in nonresectable, locally
advanced, or metastatic NSCLC,metastatic CRPC, gastric
adenocarcinoma,locally advanced squamous cell cancer of the head
and neck in combination with cisplatin and 5-FU.

10. Mechanism of Action
The unique mechanism of action for paclitaxel was initially
defined by Schiff et al, in 1979, who showed that it bound
to the interior surface of the microtubule lumen at binding
sites completely.
The taxanes profoundly alter the tubulin dissociation rate
constants at both ends of the microtubule, suppressing
treadmilling and dynamic instability.
Dose-dependent taxane β-tubular binding induces mitotic
arrest at the G2/M transition and induces cell death.

11. Peripheral neuropathy is a common dose-limiting toxicity across
the antimicrotubule agents and likely is a result of their direct
effect on microtubules.
Studies have shown that they inhibit anterograde and/or
retrograde fast axonal transport and can explain the
demyelinating “dying back” pattern seen and the vulnerability
of sensory neurons with the longest axonal projections.
Recent evidence suggests that microtubule inhibitors have
collateral effects during interphase that lead to cell death.
For instance, paclitaxel-stabilized microtubules serve as a
scaffold for the binding of the death-effector domain of pro-
caspase-8, and thereby enabling a caspase-8 downstream
proteolytic cascade.

12. This caspase-8–dependent mechanism also serves as an important basis
for the understanding of the loss of function and low expression of
the breast cancer, early onset gene (BRCA1) association with
resistance to taxane therapy.
Another mechanism of the anticancer effect of taxanes is currently
being elaborated and is tied to the B-cell lymphoma-2 (Bcl-2)
antiapoptosis family of proteins.
Paclitaxel has been shown to cause the phosphorylation of Bcl-2 and
the sequestration of Bak and Bim; however, this seemingly cancer-
protective phosphorylation needs to be reconciled and likely
correlates with Bcl-2–expression levels.
Interestingly, neutralizing Bcl-2 homology 3 (BH3) domains with
compounds such as ABT-737 is synergistic with docetaxel.

13. Paclitaxel (Taxol)
Indications.
Carcinomas of the –
breast
ovary
lung
Esophagus
other sites: AIDS-associated Kaposi sarcoma.

14. Clinical Pharmacology
Paclitaxel
With prolonged infusion schedules (6 and 24 hours), drug disposition is a
biphasic process with values for alpha and beta half-lives averaging
approximately 20 minutes and 6 hours, respectively.
When administered as a 3-hour infusion, the pharmacokinetics are
nonlinear and may lead to unexpected toxicity with a small dose
escalation, and loss of tumor response with a dose reduction.
Approximately 71% dose of paclitaxel is excreted in the stool via the
enterohepatic circulation over 5 days. Renal clearance of paclitaxel is
minimal, accounting for 14% of the administered dose.
Extensively metabolized by the hepatic P450 microsomal system.

15. Administration
Dose:
(1) Premedications: Dexamethasone, 20 mg PO or IV is given 12, 6, and
0.5 hours before paclitaxel; diphenhydramine, 50 mg IV, and ranitidine,
50 mg IV, given 30 minutes before administering paclitaxel.
(2) Every 3 to 4 weeks: 135 to 175 mg/m2 infused over 3 to 24 hours
(3) Weekly: 80 to 100 mg/m2 for 3 weeks with 1 week rest
Dose modification. Hematologic and with hepatic dysfunction. Use with
caution with diabetes mellitus, or prior therapy with neurotoxic drugs,
such as cisplatin.
Drug interactions.
(1) Barbiturates, phenytoin, and other drugs that the liver’s cytochrome
P450 CYP3A4 and CYP2C enzymes may affect paclitaxel metabolism.
(2) Carboplatin, cisplatin, or cyclophosphamide decrease paclitaxel’s
clearance and thus increase myelosuppression; they should be administered
after paclitaxel.

16. Toxicity
a. Dose-limiting
(1) Neutropenia, particularly in patients who were previously
received cisplatin just before paclitaxel.
(2) Hypersensitivity (up to 40%) is manifested by cutaneous
flushing, hypotension, bronchospasm, urticaria, diaphoresis,
pain, or angioedema. Reactions usually develop within 10
minutes of starting the treatment; 90% of hypersensitivity
reactions develop after the first or second dose.
(3) Peripheral neuropathy, particularly in the higher dosage
schedules Neurotoxicity occurs less frequently when infused
over 24 hours (5%) than when infused over 3 hours (25% to
75%).

17. b. Common: Alopecia (90%; usually total and sudden, within 3
weeks of treatment); thrombocytopenia, transient arthralgias
and myalgias within 3 days of treatment and lasting for about 1
week diarrhea, transient bradycardia (usually asymptomatic)
c. Occasional. Nausea, vomiting, taste changes, mucositis.
d. Rare. Paralytic ileus, generalized weakness, seizures;
myocardial infarction,interstitial pneumonia

18. Toxicity
Paclitaxel
The micelle-forming CrEL (cremophor/ethanol) vehicle, which is
required for suspension and intravenous delivery of paclitaxel,
causes its nonlinear pharmacokinetics and thereby impacts its
therapeutic index.
CrEL causes hypersensitivity reactions, with major reactions usually
occurring within the first 10 minutes after the first treatment
and resolving completely after stopping the treatment.
All patients should be premedicated with steroids, diphenhydramine,
and an H2 antagonist, although up to 3% will still have reactions.
Those who have major reactions have been rechallenged successfully
after receiving high doses of corticosteroids.

19. Neuropathy is the principal toxicity of paclitaxel.
Paclitaxel induces a peripheral neuropathy that presents in a
symmetric stocking glove distribution, at first transient and
then persistent.
A neurologic examination reveals sensory loss, and
neurophysiologic studies reveal axonal degeneration and
demyelination.
Severe neurotoxicity is uncommon when paclitaxel is given alone
at doses below 200 mg/m2 on a 3- or 24-hour schedule every 3
weeks, or below 100 mg/m2 on a continuous weekly schedule.

20. Neutropenia is also frequent with paclitaxel. The onset is usually
on days 8 to 11, and recovery is generally complete by days 15
to 21 with an every 3 weeks dosing regimen.
Neutropenia is noncumulative, and the duration of severe
neutropenia—even in heavily pretreated patients—is usually
brief.
Severity of neutropenia is related to the duration of exposure
above the biologically relevant levels of 0.05 to 0.10 μM/L,
and paclitaxel’s nonlinear pharmacokinetics should be
considered whenever adjusting dose.

21. Nanoparticle Albumin-Bound Paclitaxel (Abraxane)
Nab-paclitaxel is a solvent-free colloidal suspension made by
homogenizing paclitaxel with 3% to 4% albumin under high pressure to
form nanoparticles of ∼130 nm that disperse in plasma to ∼10 nm.
It received approval in 2005 based on results in patients with metastatic
breast cancer and is now also approved in treatment of locally advanced
or metastatic NSCLC, and in combination with gemcitabine for first-
line treatment of metastatic pancreatic adenocarcinoma.
Nab-paclitaxel likely capitalizes on several mechanisms, which include an
improved pharmacokinetic profile with a larger volume of distribution
and a higher maximal concentration of circulating, unbound, free drug;
improved tumor accumulation by the enhanced permeability and
receptor-mediated transcytosis via an albumin-specific receptor (gp60)
for endothelial transcytosis.

22. Administration:
Premedication with corticosteroids to prevent hypersensitivity
reactions is not required for Abraxane. Administer IV over 30 minutes.
Supplied as vials containing 100-mg of paclitaxel and 900 mg Of
albumin
Dose modifi cation. For neutropenia, hepatic dysfunction, and
sensory neuropathy
Dose. 260 mg/m2 IV over 30 minutes every 3 weeks
Toxicity
a. Dose-limiting. Neutropenia
b. Common. Hematosuppression, sensory neuropathy,
arthralgias/myalgia (usually transient), gastrointestinal
disturbances, alopecia, fatigue
c. Occasional. Abnormal liver function tests, fluid retention

23. nab-paclitaxel exhibits an extensive extravascular
volume of distribution exceeding that of water,
indicating extensive tissue and extravascular protein
distribution.
Some studies show that nab-paclitaxel achieves 33%
higher drug concentration over CrEL-paclitaxel.
Additionally, the maximum concentration (Cmax),
the mean plasma half-life of 15 to 18 hours.
The improved deposition of a nanoparticle, such as
nab-paclitaxel in a tumor tissue, can occur passively
through an EPR effect in areas of leaky vasculature,
sufficient vascular pore size, and decreased lymphatic
flow.

24. Docetaxel (Taxotere)
The pharmacokinetics of docetaxel on a 1-hour schedule is triexponential
and linear at doses of 115 mg/m2 or less.
Terminal half-lives ranging from 11.1 to 18.5 hours . The most important
determinants of docetaxel clearance were the body surface area (BSA),
hepatic function, and plasma α1- acid glycoprotein concentration.
Plasma protein binding is high (greater than 80%), and binding is primarily to
α1-acid glycoprotein, albumin, and lipoproteins.
The hepatic cytochrome P-450 mixed-function oxidases, particularly isoforms
CYP3A4 and CYP3A5, are principally involved in biotransformation.
The baseline level of α1-acid glycoprotein may be elevated as an acute phase
reactant in advanced disease and is an independent predictor of response
and a major objective prognostic factor of survival in patients with non–
small-cell lung cancer treated with docetaxel chemotherapy.

25. Docetaxel (Taxotere)
Indications. Cancers of the breast, lung, stomach,
esophagus, and head and neck, hormone-
refractory prostate cancer.
Pharmacology. The drug is prepared by
semisynthesis beginning with a precursor
extracted from the needles of the European yew
tree.
Metabolism. Extensively metabolized by the
hepatic P450 microsomal system. More than 75%
is excreted in feces and a small percentage in
urine.

26. Administration
Supplied as 20- and 80-mg vials in polysorbate 80, which is less
allergenic than Cremophor EL, which is used for paclitaxel.
Dose modification. Patients with elevated serum bilirubin or signifi
cantly elevated liver enzymes should generally not receive
docetaxel.
Dose
(1) 60 to 100 mg/m2 IV over 1 hour every 3 weeks; give
dexamethasone, 4 mg PO b.i.d. on the day before, the day of, and
the day after docetaxel administration to reduce the incidence and
severity of fluid retention and hypersensitivity reactions.
(2) 35 mg/m2 weekly for 3 weeks of a 4-week cycle (4 mg
dexamethasone on the morning and evening of dosing)

27. Toxicity
Dose-limiting. Myelosuppression
Common. Alopecia (80% except with the weekly schedule),
maculopapular rash and dry itchy skin, discoloration of fi nger nails;
mucositis, diarrhea; fatigue, fever.
Occasional
(1) Severe hypersensitivity reactions (<5%) despite premedications
(2) Fluid retention that is cumulative in incidence and severity (especially after
a cumulative dose of 705 mg/m2) is reversible (usually within 8 months).
(3) GI upset, severe nail reactions; hypotension; transiently elevated liver
function tests
(4) Peripheral neuropathy, which is less common than with paclitaxel, is
mainly sensory, but motor or autonomic neuropathy and CNS effects
are also seen.
d. Rare. Cardiac events

28. Docetaxel
TOXICITY
Neutropenia is the main toxicity of docetaxel.When docetaxel is administered on an
every 3 weeks schedule, the onset of neutropenia is usually noted on day 8, with
complete resolution by days 15 to 21.
Neutropenia is significantly less when low doses are administered weekly.
Hypersensitivity reactions were noted in approximately 31% of patients who received
the drug without premedications in early studies.
Symptoms include flushing, rash, chest tightness, back pain, dyspnea, and fever or
chills. Severe hypotension, bronchospasm, generalized rash, and erythema may also
occur.
Major reactions usually occur during the first two courses and within minutes after the
start of treatment. Signs and symptoms generally resolve within 15 minutes after
cessation of treatment, and docetaxel can usually be reinstituted without sequelae
after treatment with diphenhydramine and an H2-receptor antagonist.

29. Docetaxel induces a unique fluid retention syndrome
characterized by edema, weight gain, and third-space
fluid collection. Fluid retention is cumulative and is due
to increased capillary permeability.
Prophylactic treatment with corticosteroids has been
demonstrated to reduce the incidence of fluid retention.
Aggressive and early treatment with diuretics has been
successfully used to manage fluid retention.
Skin toxicity may occur in as many as 50% to 75% of
patients; however, premedication may reduce the
overall incidence of this effect.
Mild-to-moderate peripheral neurotoxicity occurs in
approximately 40% of untreated patients.

30. Cabazitaxel
Cabazitaxel is a semisynthetic derivative of the natural taxoid 10-
deacetylbaccatin III. It binds to and stabilizes the β-tubulin subunit,
resulting in the inhibition of microtubule depolymerization and cell
division, cell cycle arrest in the G2/M phase, and the inhibition of tumor
cell proliferation.
It is active against diverse cancer cell lines and tumor models that are sensitive
and resistant to docetaxel, including prostate, mammary, melanoma,
kidney, colon, pancreas, lung, gastric, and head and neck.
Cabazitaxel is a poor substrate for the membrane-associated, multidrug
resistance P-glycoprotein efflux pump; therefore, is useful for treating
docetaxel-refractory prostate cancer for which it gained FDA approval in
2010.
In addition, it penetrates the blood–brain barrier.
Cabazitaxel has a larger volume of distribution and a longer terminal half-life
(mean 77.3 hours versus 11.2 hours for docetaxel)

31. Administration. Premedicate with antihistamine
(e.g.,diphenhydramine 25 mg), corticosteroid (e.g.,
dexamethasone 8 mg), H2 antagonist (e.g., ranitidine
50mg), and antiemetic.
Dose modification: Do not administer if neutrophils are
≤1,500/μL or if there is hepatic impairment. Reduce dose
to 20 mg/m2 for prolonged neutropenia or diarrhea,
febrile neutropenia.
Dose: 25 mg/m2 IV over 1 hour every 3 weeks plus
prednisone (10 mg daily) throughout cabazitaxel
treatment.

32. Cabazitaxel
A phase III multi-institutional study of men with metastatic
castration- resistant prostate cancer who had failed
docetaxel improved overall median survival on cabazitaxel
compared to mitoxantrone.
Cabazitaxel was approved by the FDA in June 2010 to treat
metastatic castration-resistant prostate cancer in those who
had received prior chemotherapy. This was despite a higher
rate of adverse deaths (4.9%), a third of which were due to
neutropenic sepsis.
Cabazitaxel was associated with more grade 3 or 4 neutropenia
(82%).

33. Tesetaxel
Tesetaxel (DJ-927, XRP6258) is a semisynthetic, orally bioavailable
taxane currently in clinical trials in breast, gastric, and prostate cancer.
Administration in phase I and II trials has been once per week or every 3
weeks and not associated with hypersensitivity and possibly less
neurotoxicity compared to other taxanes.
Dose-limiting toxicity has been neutropenia.
Overall responses in phase II studies have been 50% and 38% in patients
treated for first- and second-line breast cancer, respectively.
A phase I/II study in advanced NSCLC showed an overall response rate
of 5.6%.
Pharmacokinetics on a schedule of every 3 weeks, a half life of ∼170
hours, and no drug interactions that have been noted.

34. VINCAALKALOIDS
The vinca alkaloids have been some of the most active agents in cancer
chemotherapy since their introduction 40 years ago. The naturally
occurring members of the family, vinblastine (VBL) and vincristine
(VCR), were isolated from the leaves of the periwinkle plant
Catharanthus roseus.
In the late 1950s, their antimitotic and, therefore, cancer
chemotherapeutic potential was discovered by groups both at Eli
Lilly Research Laboratories and at the University of Western
Ontario, and they came into widespread use for the single-agent
treatment of childhood hematologic and solid malignancies and,
shortly after, for adult hematologic malignancies.
Their clinical efficacy in several combination therapies has led to the
development of various novel semisynthetic analogs, including
vinorelbine (VRL), vindesine (VDS), and vinflunine (VFL).

35. Mechanism of Action
In contrast to the taxanes, the vinca alkaloids depolymerize microtubules and
destroy mitotic spindles. At low but clinically relevant concentrations, VBL
does not depolymerize spindle microtubules, yet it powerfully blocks
mitosis.
This has been suggested to occur as a result of the suppression of microtubule
dynamics rather than microtubule depolymerization. This group of
compounds binds to the β subunit of tubulin dimers at a distinct region
called the vinca-binding domain.
Importantly, VBL binding induces a conformational change in tubulin in
connection with tubulin self association. In mitotic spindles, the slowing of
the growth and shortening or treadmilling dynamics of the microtubules
block mitotic progression.

36. Tissue and tumor sensitivities to the vinca alkaloids, which, in
part, relate to differences in drug transport and accumulation,
also vary.
Intracellular or extracellular concentration ratios range from five-
to 500-fold depending on the individual cell type, lipophilicity,
tissue-specific factors such as tubulin isotype composition, and
tissue-specific microtubule-associated proteins (MAP).
Although the vinca alkaloids are retained in cells for long periods
of time and thus may have prolonged cellular effects,
intracellular retention is markedly different among the various
vinca alkaloids.
Newer theories of antimicrotubule agents’ mechanism of action
have emerged, suggesting that the more important target of
these drugs may be the tumor vasculature.

37. Clinical Pharmacology
The vinca alkaloids are usually administered
intravenously as a brief infusion.
The vinca alkaloids share many pharmacokinetic
properties, including large volumes of distribution, high
clearance rates, and long terminal half-lives that reflect
the high magnitude and avidity of drug binding in
peripheral tissues.
Although prolonged infusion schedules may avoid
excessively toxic peak concentrations and increase the
duration of drug exposure in plasma above biologically
relevant threshold concentrations, there is little
evidence to support the notion that prolonged infusions
are more effective than bolus schedules.

38. Vincristine(leurocristine, Oncovin, Vcr)
After conventional doses of VCR (1.4 mg/m2) given as brief infusions,
peak plasma levels approach 0.4 μmol.
VCR is metabolized and excreted primarily by the hepatobiliary
system.
The VCR metabolism is mediated principally by hepatic cytochrome P-
450 CYP3A5.
Administration. Patients receiving Vcr should be given bulk
laxatives routinely.
Administered by rapid infusion using extravasation precautions because
Vcr is a vesicant.
Dose modification. Hepatic dysfunction
Dose. 1.0 to 1.4 mg/m2 IV every 1 to 4 weeks, continuous infusion
regimens involve 0.4 to 0.5 mg/d for 4 days.

39. Toxicity
a. A dose-dependent peripheral neuropathy universally
develops. Cranial nerves and the autonomic system
may also be involved. The neuropathies usually reverse
within several months. Jaw, throat, or anterior thigh
pain occurring within hours of injection disappears
within days and usually does not recur.
(1) Dose-limiting. Severe paresthesias, ataxia, foot-
drop, muscle-wasting cranial nerve palsies, paralytic
ileus, obstipation, abdominal pain, optic atrophy,
cortical blindness, seizures
(2) Not dose-limiting. Mild hypoesthesia, mild
paresthesias, transient jaw pain, loss of deep tendon
reflexes, constipation
b. Common. Alopecia (20% to 50%)

40. Vinblastine
The clinical pharmacology of VBL is similar to that of VCR.
Peak plasma drug concentrations are approximately 0.4μm after
rapid intravenous injections of VBL at standard doses.
Like VCR, VBL disposition is principally through the
hepatobiliary system with excretion in feces.
Indications. Lymphomas, testicular carcinoma, Kaposi sarcoma.

41. Administration. Administered by rapid infusion through
the tubing of a running intravenous line with
extravasation precautions because vinblastine is a
vesicant
Dose modification. Decrease dose by 50% for patients
with serum bilirubin >3.0 mg/dL and by 75% for 3 to 5
mg/dL.
Dose. 5 mg/m2 IV every 1 or 2 weeks.
Toxicity
a. Dose-limiting. Neutropenia
b. Common. Cramps or severe pain in jaw, pharynx,
back, or limbs after injection
c. Occasional. Thrombocytopenia, anemia, alopecia
(10%); SIADH, hypertension, Raynaud phenomena,
neuropathy

42. Vinorelbine
The pharmacologic behavior of VRL is similar to that of the other vinca
alkaloids, and plasma concentrations after rapid intravenous
administration have been reported to decline in either a
biexponential or triexponential manner.
Plasma protein binding, principally to α1-acid glycoprotein, albumin,
and lipoproteins, has been reported to range from 80% to 91%, and
drug binding to platelets is extensive.
VRL is widely distributed, and high concentrations are found in
virtually all tissues, except the central nervous system.
As with other vinca alkaloids, the liver is the principal excretory organ,
and up to 80% of VRL is excreted in the feces.
The cytochrome P-450 CYP3A isoenzyme appears to be principally
involved in biotransformation.

43. Indications. Non–small cell lung cancer, ovarian cancer, breast
cancer, and Lymphoma.
Dose. 15 to 30 mg/m2 IV weekly.
Toxicity
a. Dose-limiting. Myelosuppression, especially neutropenia
b. Common. Fatigue; mild to moderate peripheral neuropathy;
nausea, vomiting, constipation, diarrhea
c. Occasional. Stomatitis; jaw pain, myalgias/arthralgias; allergic-
type pulmonary reactions; nausea, vomiting, transient
abnormalities in LFTs

44. Vinflunine (VFL)
VFL is a novel semisynthetic microtubule inhibitor with a
fluorinated catharanthine moiety, which translates into lower
affinity for the vinca binding site on tubulin and, therefore,
different quantitative effects on microtubule dynamics.
The low affinity for tubulin may be responsible for its reduced
clinical neurotoxicity. Despite this lower affinity, it is more
active in vivo than other vinca alkaloids, and resistance
develops more slowly.
Its volume of distribution is large, and has a terminal half-life of
nearly 40 hours.
The only active metabolite is 4-O-deacetylvinflunine, which has a
terminal half-life approximately 5 days longer than that of the
parent compound.

45. Toxicity
Despite close similarities in structure, the vinca alkaloids
differ in their safety profiles. Neutropenia is the principal
dose-limiting toxicity of VBL and VRL.
Thrombocytopenia and anemia occur less commonly. The
onset of neutropenia is usually day 7 to 11, with recovery by
day 14 to 21, and can be potentiated by hepatic dysfunction.
Gastrointestinal autonomic dysfunction, as manifested by
bloating, constipation, ileus, and abdominal pain, occur
most commonly with VCR or high doses of the other vinca
alkaloids.
Mucositis occurs more frequently with VBL than with VRL
and is least common with VCR. Nausea, vomiting, diarrhea
and pancreatitis also occur to a lesser extent.

46. VCR principally induces neurotoxicity characterized by a peripheral,
symmetric mixed sensory motor and autonomic polyneuropathy.
Toxic manifestations include constipation, abdominal cramps, paralytic
ileus, urinary retention, orthostatic hypotension, and hypertension.
Its primary neuropathologic effects are due to interference with axonal
microtubule function. Early symmetric sensory impairment and
paresthesias can progress to neuritic pain and loss of deep tendon
reflexes with continued treatment, which may be followed by foot
drop, wrist drop, motor dysfunction, ataxia, and paralysis.
Cranial nerves are rarely affected because the uptake of VCR into the
central nervous system is low. Severe neurotoxicity occurs
infrequently with VBL and VDS.

47. In adults, neurotoxicity may occur after treatment with cumulative doses as
little as 5 to 6 mg, and manifestations may be profound after cumulative
doses of 15 to 20 mg.
The vinca alkaloids are potent vesicants. To decrease the risk of phlebitis, the
vein should be adequately flushed after treatment. If extravasation is
suspected, treatment should be discontinued, aspiration of any residual drug
remaining in the tissues should be attempted, and prompt application of
heat for 1 hour four times daily for 3 to 5 days can limit tissue damage.
Hyaluronidase, 150 to 1,500 U (15 U/mL in 6 mL 0.9% sodium chloride
solution) subcutaneously, through six clockwise injections in a
circumferential manner using a 25-gauge needle (changing the needle with
each new injection) into the surrounding tissues may minimize discomfort
and latent cellulitis.
Acute cardiac ischemia, chest pains without evidence of ischemia, fever,
Raynaud syndrome, and pulmonary and liver toxicity (transaminitis and
hyperbilirubinemia) have also been reported with use of the vinca
alkaloids. All of the vinca alkaloids can cause a syndrome of inappropriate
secretion of antidiuretic hormone (SIADH).

48. MICROTUBULE ANTAGONISTS
Estramustine Phosphate Estramustine is a conjugate of nor-nitrogen
mustard linked to 17β-estradiol by a carbamate ester bridge.
Estramustine phosphate received regulatory approval in the United
States in 1981 for treating patients with castration-resistant prostate
cancer (CRPC).
Estramustine has significant activity in CRPC and had been used in
combination with VBL or docetaxel. However, phase III trials in
patients with CRPC showed that when combined with docetaxel,
there is no added benefit to overall survival compared to docetaxel
alone.
This agent depolymerizes microtubules and microfilaments, binds to
and disrupts MAPs, and inhibits cell growth at high concentrations,
resulting in mitotic arrest and apoptosis in tumor cells.

49. Indication. Progressive prostate cancer.
Pharmacology. Structurally, estramustine is a combination of estradiol
phosphate and nornitrogen mustard.
Metabolism. Rapidly dephosphorylated in GI tract and metabolized primarily
in the liver. About 20% of the drug is excreted in the urine.
Toxicity. Similar to estrogens
a. Dose limiting. Thromboembolism
b. Common. Diarrhea; nausea and vomiting (usually mild); skin rash.
Gynecomastia in up to 50% of patients
Administration. Contraindicated in patients with active thrombophlebitis or
thromboembolic disorders
Dose. 600 mg/m2/d in three divided doses; taken with water 1 hour
before meals or 2 hours after meals. Calcium-rich foods may impair drug
absorption.

50. Epothilones
The epothilones are macrolide compounds that were initially
isolated from the mycobacterium Sorangium cellulosum.
They exert their cytotoxic effects by promoting tubulin
polymerization and inducing mitotic arrest.
In general, the epothilones are more potent than the taxanes. In
contrast to the taxanes and vinca alkaloids, overexpression
of the efflux protein P-glycoprotein minimally affects the
cytotoxicity of epothilones.
Epothilones include the natural epothilone B and several
semisynthetic epothilone compounds such as aza-epothilone
B (ixabepilone), epothilone D (deoxyepothilone ), and a
fully synthetic analog, sagopilone.

51. Ixabepilone is FDA approved for the treatment of patients with
breast cancer.
It is active in breast cancer previously treated with paclitaxel or
docetaxel.
The principal toxicities observed include neutropenia and
peripheral neuropathy.
It also has been evaluated in other solid tumors such as ovarian,
prostate, and renal cell carcinomas.
Epothilones are still undergoing evaluations in several clinical
trials.
Pharmacokinetics have shown large volume of distribution and
low body clearance.

52. Maytansinoids and Auristatins:
Antibody drug conjugates (ADC) were first attempted with delivery of
doxorubicin. Although tissue localization seemed promising, it
became clear that the delivery of more potent chemotherapeutics
was necessary.
One of the major advances for the promise of ADC came with the
discovery and development of highly potent anticancer compounds
such as calicheamicins, maytansinoids, and auristatins.
Gemtuzumab ozogamicin was the first ADC using calicheamicin, a
potent DNA minor groove binder (and not a microtubule agent),
approved in 2000 although withdrawn from the market in 2013 due
to failed confirmatory studies.
Maytansinoids and auristatins are unrelated, although are both tubulin-
binding agents of the vinca binding site and inhibit tubulin
polymerization.

53. Drug maytansinoid-1 (DM1) is the chemotherapeutic delivered
using a thioether linker in the ADC ado-trastuzumab
emtansine (T-DM1) that was FDA approved for patients
with HER2- positive metastatic breast cancer previously
treated with trastuzumab and taxane chemotherapy.
Monomethyl auristatin E (MMAE) is linked to a monoclonal
antibody against CD30 as an ADC and approved for
refractory Hodgkin lymphoma or anaplastic large cell
lymphoma.
Dose-limiting toxicities include thrombocytopenia,
hyperglycemia, diarrhea, and vomiting.
Most common side effects in this heavily pretreated population
includes peripheral neuropathy (42%), nausea (35%), and
fatigue (34%).

54. MITOTIC MOTOR PROTEIN INHIBITORS
Aurora Kinase and Pololike Kinase Inhibitors
Aurora kinases are serine/threonine kinases crucial for mitosis
in their recruitment of mitotic motor proteins for spindle
formation.
They are particularly overexpressed in high growth rate
tumors.
Aurora A and B kinases are expressed globally throughout all
tissues, and Aurora C kinase is expressed in testes and
participates in meiosis.
Aurora A kinase is expressed and frequently amplified in many
epithelial tumors and implicated in the microtubule-targeted
agent-resistant phenotype.

55. Aurora A kinase interacts with p53, and there is evidence
that p53 wild-type tumors are more sensitive to aurora
A kinase inhibitors than p53 mutant tumors.
The main dose-limiting toxicity of these agents is
neutropenia.
Pololike kinases (PLKs) are serine or threonine kinases
crucial for cell cycle process.
Overexpression of PLKs has been shown to be related to
histologic grading and poor prognosis in several types
of cancer.
BI-2536 and ON01910 are PLK inhibitors in early clinical
development.

56. Kinesin Spindle Protein Inhibitor
Ispinesib
Kinesin spindle protein (KSP) is a kinesin motor protein
required to establish mitotic-spindle bipolarity.Several KSP
inhibitors have been evaluated in early phase clinical trials.
Ispinesib is a small-molecule inhibitor of KSP ATPase and has
been evaluated in two different schedules.
The dose-limiting toxicity is neutropenia.
Ispinesib was found to be inactive in phase 2 studies
evaluating efficacy in patients with castration-resistant and
largely docetaxel-resistant prostate cancer, advanced renal
cancer, and head and neck cancer.

57. MECHANISMS OF RESISTANCE TO MICROTUBULE
INHIBITORS
Drug resistance is often complex and can involve diverse
mechanisms such as
(1) factors that reduce the ability of drugs to reach their
cellular target (e.g., activation of detoxification pathways
and decreased drug accumulation).
(2) modifications in the drug target.
(3) events downstream of the target (e.g., decreased sensitivity
to, or defective, apoptotic signals).
Many tubulin binding agents are substrates for multidrug
transporters such as P-glycoprotein and the multidrug
resistance gene (MDR1).
.

58. An increasing number of studies suggest that the expression of
individual tubulin isotypes are altered in cells resistant to
antimicrotubule drugs and may confer drug resistance.
Inherent differences in microtubule dynamics and drug
interactions have been observed with some isotypes in vitro
and in vivo.
Several taxane-resistant mutant cell lines that have structurally
altered α- and β-tubulin proteins and an impaired ability to
polymerize into microtubules have also been identified.
As opposed to taxanes, resistance to vinca alkaloids has been
associated with decreased class II β-tubulin expression.

59. The MDR1-encoded gene product MDR1 (ABC subfamily B1;
ABCB1) and MDR2 (ABC subfamily ABCB4) are the best
characterized ABC transporters thought to confer drug
resistance to taxanes.
MDR-related taxane resistance can be reversed by many classes
of drugs, including the calcium channel blockers, cyclosporin
A, and antiarrhythmic agents.
However, the clinical utility of this approach has never been
proven, despite several clinical trials.
The role of ABC transporters in resistance to microtubule
inhibitors remains to be determined

62. Thank You.