1.
SPINDLE POISONS
Tulasi Raman
Moderator: Dr. Padmavathi S.

2.
Mitotic Spindle

3.
The Cell Cycle
G1
S
G2
M G0

4.
Vinca Alkaloids
Taxanes
Estramustine
Epothilones
Colchicine
Benzimidazoles
Griseofulvin

5.
VINCA ALKALOIDS
1. Vinblastine
2. Vincristine
3. Vinorelbine
4. Vindesine

6.
Source
• Madagascar periwinkle plant
– Catharanthus roseus
– Vinca rosea
• Hypoglycemic effects in diabetes.

7.
Mechanism of action
• Cell-cycle–specific
• Cell division arrests in metaphase.
• Bind specifically to β-tubulin and to block its
polymerization with α-tubulin into microtubules.
• In absence of an intact mitotic spindle, duplicated
chromosomes cannot align along the division
plate. They disperse throughout the cytoplasm or
may clump in unusual groupings
• Apoptosis

8.
Drug Resistance
• Antitumor effects are blocked by multidrug
resistance mediated by the mdr gene and its
glycoprotein
– Ca2+ channel blockers such as verapamil can reverse
resistance of this type in vitro
• MRP and the closely related breast cancer
resistance protein, may mediate multidrug
resistance
• Mutations in β-tubulin or in the relative
expression of isoforms of β-tubulin

9.
Pharmacokinetics
• Metabolised by liver cytochromes
– Hepatic dysfunction (bilirubin >3 mg/dL), a 50-
75% reduction in dose
• Excreted in bile
• < 15% excreted unchanged in urine

10.
Vinblastine
• Given intravenously
• Single dose of 0.3 mg/kg of body weight
– Myelosuppression reaches its maximum in 7-10
days. If a moderate level of leukopenia (~3000
cells/mm3) is not attained, the weekly dose may
be increased gradually by increments of 0.05
mg/kg of body weight.
• Doses should be reduced by 50% for patients
with plasma bilirubin >1.5 mg/dL.

11.
• Clinical Applications
– Metastatic testicular tumor
• Vinblastine, Bleomycin and Cisplatin
– Hodgkins disease
• ABVD - Adriamycin, Bleomycin, Vinblastine and
Dacarbazine

12.
Toxicity
– Leukopenia
• Occurs within 7-10 days, after which recovery ensues within
7 days
– Mild neurological manifestations
– GI disturbances
• Nausea, Vomiting , Diarrhoea, Anorexia
– Syndrome of inappropriate secretion of antidiuretic
hormone
– Extravasation during injection may lead to cellulitis
and phlebitis

13.
Vincristine
• Given Intravenously
• 2 mg/m2 of body surface area at weekly or
longer intervals
• Doses should be reduced by 50% or 75% for
patients with plasma bilirubin >1.5 mg/dL or
>3 mg/dL

14.
• Clinical Applications
– With glucocorticoids is the treatment of choice to
induce remissions in childhood leukemia
– In combination with alkylating agents and
anthracycline for pediatric sarcomas

15.
Toxicity
– Neurological symptoms
• Motor dysfunction
– Severe constipation
• Colicky abdominal pain and obstruction
– May be prevented by a prophylactic program of laxatives and bulk-forming
agents
– Alopecia
• Reversible, frequently without cessation of therapy
– Modest Leukopenia
• Thrombocytopenia
– Anemia
– GI cholic and Obstipation
– Syndrome of inappropriate secretion of antidiuretic hormone
• Inadvertent injection into the CSF causes a devastating and
often fatal irreversible coma and seizures

16.
Vinorelbine
• In normal saline as an intravenous infusion
over 6-10 minutes
• Doses of 30 mg/m2 either weekly or for 2 out
of every 3 weeks.

17.
• Clinical Applications
– With cisplatin for the treatment of non–small cell
lung cancer
– Oral formulation is active in non–small cell lung
carcinoma

18.
Toxicity
– Granulocytopenia
– Modest cytopenia
– Less neurotoxicity
– Allergic reactions
– Mild reversible changes in liver enzymes
• Doses should be reduced by 50% or 75% in
patients with plasma bilirubin 2.1-3 mg/dL or
>3 mg/dL

19.
TAXANES
1. Paclitaxel
2. Docetaxel

20.
Mechanism of Action
• It binds specifically to the B-tubulin subunit of
microtubules and antagonizes the disassembly
of this key cytoskeletal protein
• Cell killing is dependent on both drug
concentration and duration of cell exposure
• Cell death occurs by apoptosis

21.
Drug Resistance
• Increased expression of the mdr-1 gene and
its product, P-glycoprotein
• B-tubulin mutations
• Increase in survivin, an anti-apoptotic factor
• Increase in aurora kinase, an enzyme that
promotes completion of mitosis
• Upregulating the BIII-isoform of tubulin

22.
Drug interactions
• The sequence of cisplatin preceding paclitaxel
decreases paclitaxel clearance and produces
greater toxicity
• Paclitaxel decreases doxorubicin clearance and
enhances cardiotoxicity

23.
Paclitaxel
• Source
– Bark of the Western yew tree
– Semisynthesis from 10-desacetylbaccatin

24.
• Cremaphor
– 50% ethanol and 50% polyethoxylated castor oil
• Responsible for a high rate of hypersensitivity reactions
• Pretreatment with a histamine H1-receptor antagonist such
as diphenhydramine, an H2-receptor antagonist such as
cimetidine and a glucocorticoid such as dexamethasone
• Albumin bound Nanoparticle
– Soluble in aqueous solutions
– Increased peripheral neuropathy
– Not be given to patients with decreased absolute
neutrophil count

25.
Pharmacokinetics
– 3 hour infusion every 3 weeks
– 1 hour infusion weekly
– Metabolised by hepatic cytochromes
• 6-OH paclitaxel, inactive
– < 10% excreted in urine unchanged
– Clearance is non-linear
• Decreases with increased dose
– Presence of hepatic metastases >2 cm in diameter
decreased clearance and led to high drug
concentrations in plasma and greater
myelosuppression.

26.
Toxicity
– Neutropenia
– Stock & Glove sensory neuropathy
– Myalgias
– Mucositis
– Hypersensitivity reactions
– Asymptomatic bradycardia
– Silent ventricular tachycardia

27.
Docetaxel
• Semi-synthetic
• Administered in polysorbate 80
• Pharmacokinetics
– Linear
– Heaptic cytochromes
• Inactive metabolites

28.
Toxicity
– Increased neutropenia
– Fluid retention
• Peripheral edema
• Pleural fluid
• Peritoneal fluid
• Pulmonary edema
• Progressive interstitial pneumonitis
• Respiratory failure
– Oral dexamethasone ameliorates fluid retention

29.
Uses
• Metastatic ovarian cancer
• Breast cancer
• Lung cancer
• GI cancer
• Genitourinary cancer
• Head and neck cancer

30.
Estramustine
• Combination of estradiol coupled to
normustine through a carbamate link
• Mechanism of action
– Binds to B tubulin and microtubule-associated
proteins, causing microtubule disassembly

31.
Pharmacokinetics
– Orally
– Extensive first pass metabolism
– Oxidised 17 keto derivative
• Active
– Excreted in faeces
• Inactive metabolites
– Inhibits clearance of taxanes

32.
Uses
– Prostatic Cancer
• Metastatic
• Locally advanced hormone refractory

33.
Toxicity
– Myelosuppression
– Estrogenic side effects
• Gynecomastia
• Impotence
• Elevated risk of thrombosis
• Fluid retention
– Hypercalcemia
– Acute attacks of porphyria
– Impaired glucose tolerance
– Hypersensitivity reactions
• angioedema.

34.
Epothilones
• Sorangium cellulosum
– Myxobacterium
• Isolated from soil on the bank of the Zambezi River in
southern Africa
• Mechanism of Action
– Bind to B-tubulin
– Microtubule stabilisation
– Cell-cycle arrest at the G2-M interface
– Apoptosis

35.
Resistance
– Less susceptible to P-glycoprotein-mediated
multidrug resistance
– Mutation of the B-tubulin binding site
– Upregulation of isoforms of B-tubulin

36.
Pharmacokinetics
– Ixabepilone
• Intravenously
– Less solubile
• Polyoxyethylated castor oil / ethanol
– Hepatic cytochrome clearance
• Dose
– 40 mg/m2 over 3 hours every 3 weeks

37.
Uses
– Metastatic Breast Clearance
• Monotheraphy
• Combination therapy
– Anthracyclines
– contraindicated in patients with a baseline neutrophil count
<100,000
– cells/mm3, serum transaminases >2.5 x ULN or bilirubin
above normal

38.
Toxicity
– Neutropenia
– Peripheral sensory neuropathy
– Fatigue
– Diarrhea
– Asthenia

39.
BENZIMIDAZOLES
• Thiabendazole
• Mebendazole
• Albendazole

40.
Mechanism of action
• Inhibits of microtubule polymerization by binding
to β-tubulin
• Higher affinity for parasite β -tubulin
• Inhibition of mitochondrial fumarate reductase
• Reduced glucose transport
• Uncoupling of oxidative phosphorylation

41.
Pharmacokinetics
• Thiabendazole is soluble in water
• Mebendazole and albendazole are poorly soluble
• Low systemic bioavailability
– poor absorption and
– Rapid first-pass hepatic metabolism
• 95% bound to plasma proteins
• Active metabolite - Mebendazole
• Excreted in Bile as Inactive metabolites

42.
• Albendazole absorption is enhanced by the
• presence of fatty foods and possibly by bile salts.
• Rapidly metabolized in the liver to albendazole
sulfoxide, which has potent anthelmintic activity
• 70% bound to plasma proteins
• Excreted mainly in the urine

43.
Uses
• Thiabendazole
– Cutaneous larva migrans (creeping eruption)
– Strongyloidiasis
• Mebendazole
– Enterobiasis, a single 100-mg tablet
– Ascariasis, Trichuriasis, or Hookworm infections,
100mg BD for 3 days

44.
• Albendazole
• Enterobiasis, ascariasis, trichuriasis, and
hookworm), single oral 400-mg dose by adults
• and children >2 years of age.
• In children between the ages of 12 and 24
months, the WHO recommends a reduced
dose of 200 mg.

45.
• Drug of choice for treating cystic hydatid
disease due to Echinococcus granulosus
– 400mg BD for 1-6 months
• Only drug available with useful activity against
alveolar echinococcosis caused by E.
multilocularis
• Parasiti-static rather than -cidal, and lifelong
therapy with or without surgical intervention

46.
• Preferred treatment of neurocysticercosis caused
by larval forms of Taenia solium
• recommended dosage is 400 mg given twice a
day for adults for 8-30 days
• Glucocorticoid therapy is usually begun before
initiating albendazole therapy to reduce the
incidence of side effects resulting from
inflammatory reactions to dead and dying
cysticerci.

47.
GRISEOFULVIN
• Inhibits microtubule function
– Disrupts assembly of the mitotic spindle
• Binding sites on the microtubular protein
are distinct
• In addition, interacts with microtubule-
associated protein

48.
Pharmacokinetics
• Improved absorption when the drug is taken with
a fatty meal.
• Micro-sized and ultra-micro-sized powders
• Primary metabolite is 6-methylgriseofulvin.
• Griseofulvin is deposited in keratin; the drug is
tightly bound to, and persists in, keratin,
providing prolonged resistance to fungal invasion.

49.
Uses
• Tinea capitis
• Tinea cruris
• Tinea corporis
• Tinea of the hands & beard
• Tinea pedis
• Topical Therapy is sufficient in most cases

50.
COLCHICINE
• Rx of Gout
• Inhibits tubular formation
– Anti-mitotic effects
– Release of histamine-containing granules from
mast cells
– Secretion of insulin from pancreatic cells
– Movement of melanin granules in melanophores

51.
• May alter neutrophil motility
• Decreases the crystal-induced secretion of
chemotactic factors and superoxide anions by
activated neutrophils.
• Limits neutrophil adhesion to endothelium by
modulating the expression of endothelial
adhesion molecules.

52.
Pharmacokinetics
• Oral absorption is rapid but variable
• 50% of colchicine is protein bound
• Significant enterohepatic circulation
• Dose must be decreased for patients with
impaired renal function.
• 10-20% is excreted in the urine

53.
• Acute Gout
– Two doses taken 1 hour apart: 1.2 mg (two
tablets) at the first sign of a gout flare followed by
0.6 mg (one tablet) 1 hour later.
• Dose for prophylaxis is
– 0.6 mg taken orally 3 or 4 days/wk for patients
who have <1 attack per year
– 0.6 mg daily for patients who have >1 attack per
year
– 0.6 mg two or three times daily for patients who
have severe attacks.

54.
THANK YOU !