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75 terms

Taxanes Vinca alkaloids Antimetabolites

Chemotherapy
STUDY
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Taxane Agents
Cabazitaxel (Jevtana)
Docetaxel (Taxotere)
Paclitaxel (Taxol)
Albumin-bound paclitaxel (Abraxane)
Ixabepilone (Ixempra)
Vinca Alkaloids
Vinblastine
Vinorelbine
Vincristine
Anti-mitotic Agent
Eribulin (Halaven)
Microtubules fjunction
Principle components of the mitotic spindle apparatus
Separate the duplicate set of chromosomes during mitosis
Function to maintain the scaffolding and shape of the cell
Assembled by linear stacking of alternating units of alpha and beta tubulin
Tubulin polymerization function
Nucleation - elongation mechanism that allows a microtubule to shorten and elongate according the the cell cycle
Microtubules are in a constant state of motion (assembling and
disassembling)
Microtubule Dynamics
Treadmilling: net growth at one end of the microtubule (plus
end) and net shortening at the opposite end (minus end)
Dynamic instability: microtubule ends switch spontaneously
between states of slow sustained growth and rapid shortening
Microtubule have 2 ends
Plus end: More rapid and polymerization
Minus end: Faster release Of subunits (depolymerization)
Taxane Agents Mechanism of Action
M phase specific,
Binds β-tubulin subunit of the microtubule and prevents disassembly (depolymerization) of the tubulin
Results in formation of stable, nonfunctional microtubules
Cell is unable to complete cell division and undergoes
apoptosis
Paclitaxel (Taxol) Uses
Majority of solid tumors
Breast, Lung, Ovarian,
Testicular, Head and Neck,
among others
Paclitaxel (Taxol) Toxicities
Neutropenia (DLT)
Nausea / Vomiting
Peripheral neuropathy
Alopecia
Arthralgia / Myalgia
Anaphylactic
hypersensitivity (due to
Cremaphor)
Flushing / Rash
Cardiac arrhythmias
Paclitaxel (Taxol) Dose Adjustment
Hepatic dysfunction
Hepatic metabolism
through CYP 2C8
Paclitaxel (Taxol) Special Compounding
Drug is diluted in 50/50
Cremaphor (castor oil) and
alcohol
DO NOT MIX in PVC
Plasticizer DHEP leaches
into solution = Toxic
Paclitaxel (Taxol) Premedications
(30 minutes prior)
Histamine-2 receptor
antagonist
Famotidine 20mg IV
Diphenhydramine 25 mg
IV
3 doses of dexamethasone:
12 - 20 mg PO at 12, 6 and
1 hour prior to paclitaxel
Antiemetics
Albumin-Bound Paclitaxel (Abraxane)
Indicated only in metastatic breast cancer following
progression of an anthracycline-based therapy
Similar toxicities to paclitaxel
LOWER risk of hypersensitivity reaction
HIGHER rate of peripheral neuropathy and neutropenia
Dosing adjustments for hepatic dysfunction
Docetaxel (Taxotere) Uses
Solid tumors primarily
Prostate, Breast, Lung,
Ovarian, Bladder, Head
and Neck
Docetaxel (Taxotere) Toxicities
Neutropenia (DLT)
Peripheral neuropathy
Alopecia
Fluid retention
Anaphylactic
hypersensitivity (due
toTween 80)
Arthralgia / Myalgia
Nausea / Vomiting
Flushing / Rash
Docetaxel (Taxotere) Dose Adjustment
Hepatic dysfunction
Hepatic metabolism through
CYP 3A4/5*
Docetaxel (Taxotere) Special Compounding
Drug is diluted in Polysorbate
80 and alcohol
DO NOT MIX in PVC
Plasticizer DHEP leaches into
solution = Toxic
Docetaxel (Taxotere) Premedications (30 minutes prior)
Diphenhydramine 25 mg
Dexamethasone 8mg PO BID
beginning day before
docetaxel and continuing for
3 days (reduces edema)
Antiemetics
Ixabepilone (Ixempra) approved for
Only approved for use in breast cancer after failure of
anthracyclines, taxanes and capecitabine
Ixabepilone (Ixempra) Toxicities
Peripheral neuropathy (DLT)
Neutropenia
Myocardial ischemia
Myalgia
Fatigue
Nausea
Anaphylactic hypersensitivity
(contains Cremaphor*)
Premedicate like paclitaxel
Ixabepilone (Ixempra) dosing limitations
Dose reduce in hepatic dysfunction
Ixabepilone (Ixempra) Epithilone Drug Class MOA:
Binds to beta-tubulin (occupies different binding site than taxanes)
5 - 25x more potent than
paclitaxel
Eribulin (Halaven) MOA
non-taxane microtubule inhibitor, halichondrin B analog which inhibits growth phase of microtubules by inhibiting formation of
mitotic spindle
Eribulin (Halaven) Uses
Metastatic breast cancer
Eribulin (Halaven) Toxicities
Myelosuppression
Neutropenia
Anemia
QTc prolongation
Peripheral neuropathy
Alopecia
Cabazitaxel (Jevtana) Uses
Hormone refractory metastatic prostate cancer
Cabazitaxel (Jevtana) Toxicities
Neutropenia
Neuropathy
Hypersensitivity reaction
(contains polysorbate 80)
Premediate like paclitaxel
Nausea / vomiting /
diarrhea
Arthralgia
Alopecia
Vinca Alkaloids MOA
Inhibit tubulin polymerization Block ability to form a
mitotic spindle
Cell is unable to complete cell division and undergoes
apoptosis
Taxanes Vinca alkaloids MOA diagram
Vincristine (Oncovin) Uses
Leukemia, Lymphoma
Vincristine (Oncovin) Toxicities
Peripheral neuropathy
(DLT)
Paralytic ileus
Prophylactic stool
softeners
2 tabs QHS - titrate to regulate bowel movements
SIADH
Minimal nausea
MAX dose = 2 mg Vesicant
Vincristine (Oncovin) dose adjustments
Hepatic
Requires dosing
adjustment for hepatic
insufficiency
Vinblastine (Velban) Uses
Lymphoma, melanoma
Vinblastine (Velban) Toxicities
Neutropenia (DLT)
Thrombocytopenia
Alopecia
Mild peripheral neuropathy
SIADH
Minimal nausea
Vesicant
Vinblastine (Velban) dose adjustments
Requires dosing adjustment for hepatic insufficiency
Compounding Vinca Alklaloids
FATAL if given by intraTHECAL route
Slow, painful death from myeloencephalopathy
Ascending motor and sensory neuropathy
World Health Organization recommends compounding these
drugs in a piggyback
NO Syringes = NO confusion for intrathecal administration
"S" Phase Agents Antimetabolites
Methotrexate
Pemetrexed
Fluouracil / Capecitabine
Mercaptopurine
Thioguanine
Fludarabine
Pentostatin
Gemcitabine
Cytarabine
Azacytidine
Decitabine
Antifolate Drugs
Methotrexate and Pemetrexed
S Phase Specific Activity antifolate Deficiency
impairs thymidylate and purine synthesis (DNA synthesis)
Megaloblastic anemia
Methotrexate (Trexall) Uses
Leukemia, Lymphoma
Various solid tumors
(sarcoma, breast, head and
neck, choriocarcinoma)
Non-oncology
Psoriasis, rheumatoid arthritis,
Crohn's disease, graft versus
host therapy, abortifacient
Methotrexate (Trexall) MOA
Inhibits the enzyme dihydrofolate reductase
DHFR replenishing cell's tetrahydrofolate supply
Increasing levels of dihydrofolate inhibits activity of thymidylate synthase
Blockade of DHFR = inhibition of thymidylate and purine
synthesis
Methotrexate (Trexall) Special Notes
Wide variability in dosing!
2.5 mg once a week - 20 grams once a month
PO, IV, can give intrathecally
Eliminated in urine -adjust dose for renal dysfunction
High protein binding
3rd space fluid collection (pleural effusions, ascites)
Methotrexate (Trexall) Toxicities
Mucositis
Myelosuppression (neutropenia, thrombocytopenia)
Renal toxicity
Pneumonitis
Alopecia
Infertility
High-Dose Methotrexate can
High - dose methotrexate, Requires urine alkalinization (pH >
7.5), Requires high volume hydration (250 ml/m2/hr) for renal
protection, Requires leucovorin rescue which will rescue both healthy and malignant cells
High-Dose Methotrexate Leucovorin rescue
Initiated > 24 hours after the dose of methotrexate
20 mg IV/PO Q6H
Increase dose based on algorithm
Treat with leucovorin until methotrexate level < 1 x 10 -7 molar
Mucositis Tx
Supportive Care
IV/PO pain medication
Saliva substitute
Soft tooth brush and baking soda water rinse
Cryotherapy
"Magic Mouth Wash"
Hydrocortisone 110 mg IV, Diphenhydramine elixer 120 mL, Nystatin
suspension 120 mL (may substitute Maalox, tetracycline, sucralfate)
5 - 10 mL PO Q4H prn pain
+/- viscous lidocaine 2% (beware of cardiac adverse effects)
Pemetrexed (Alimta) Uses
Non-small cell lung cancer, drug of choice for mesothelioma
Pemetrexed (Alimta) MOA
Multi-targeted
Inhibits thymidylate synthase
Weakly inhibits DHFR
Inhbitis GARFT (glycinamide ribonucleotide formyltransferase) - enzyme necessary for purine synthesis
Pemetrexed (Alimta) Toxicities and Supportive Care
Myelosuppression
At least 7 days prior to 1st dose:
Cyanocobalamin 1000 mcg IM then every 9 weeks
Folic acid 1 mg PO daily
Pruritic rash (40%)
Dexamethasone 4 mg BID day -1, day 0 and day +1 t
Prevention of rash
Antifolate mechanism of action
Fluouracil (5-FU, Adrucil) is
Fluorinated analog of naturally occurring pyrimidine of uracil that is S-phase specific
Fluouracil (5-FU, Adrucil) MOA
Monophosphate form of 5-FU (F-dUMP) inhibits thymidylate
synthase
Competes with natural substrate, dUMP for
thymidylate synthase binding
dUMP required to make thymidine (building block of DNA)
Triphosphate form of 5-FU (FUTP) incorporates into RNA as
a false base pair
5-FU drug Interactions
Leucovorin
Addition of folates during 5-FU infusion increases the stability of the 5-FU monophosphate - thymidine sythase bond
Results in increased
cytotoxic activity
Warfarin
Increased PT/INR
Phenytoin
Increased phenytoin levels
Radiation
Radio-sensitizer
Fluoruracil Uses
Breast, Colorectal, Gastric, Esophageal, Head and Neck, Pancreatic, Cervical Cancer
Fluoruracil Toxicity
Myelosuppression
Mucositis
Diarrhea
Palmar-Plantar erythema (Hand-Foot Syndrome)
Photosensitivity
Mild Nausea
Neurotoxicity
Capecitabine (Xeloda) FDA indicated
Colorectal Cancer (CRC)
Single agent for adjuvant therapy after complete tumor
resection*
Single agent, first line therapy in metastatic CRC

Metastatic Breast Cancer
Single agent
In combination with docetaxel or lapatinib
Antipyrimidine Antimetabolites Cytidine Analogues
Cytarabine
Gemcitabine
Azacytidine
Decitabine
Cytarabine (Ara-C) Uses
Leukemia and Lymphoma
No activity in solid tumors
Cytarabine (Ara-C) Elimination
Enzyme cytidine deaminase
deactivates Ara-C
Enzyme present in low levels in
the CNS
Effective for intrathecal
administration
Dose adjust for renal dysfunction
(increased neurotoxicity)
Cytarabine (Ara-C) MOA
Analog of deoxycytidine
Incorporates into DNA
Terminates chain elongation
Inhibits DNA polymerase
Cytarabine is phosphorylated to an active triphosphate form (aca-CTP) within tumor cells
Cytarabine (Ara-C) Adverse Effects
Myelosuppression
Conjunctivitis
Nausea / Vomiting
Skin rash (palmar-plantar)
Cerebellar toxicity
LFT elevation (transient)
Diarrhea
Gemcitabine (Gemzar) Uses
Bladder, Pancreatic, Lung, Breast,
Ovarian Cancer
Radiation sensitizer
Gemcitabine (Gemzar) Toxicities
Edema
Acute respiratory distress syndrome
Rash
Nausea / Vomiting
Thrombocytopenia - DLT
Flu-like symptoms
Transient elevation in LFTs
Gemcitabine (Gemzar) MOA
Analog of deoxycytidine
Incorporates into DNA
Terminates chain elongation
Competes with the natural substrate, dCTP (deoxycytidine triphosphate), for DNA incorporation
Inhibits DNA polymerase
Inhibits DNA synthesis
Inhibiting an enzyme responsible for the production of deoxynucleotides, ribonucleotide reductase
Azacytidine (Vidaza) & Decitabine (Dacogen) Uses and MOA
Myelodysplastic syndrome
Acute myeloid leukemia
Limited activity

Hypomethylating agents
Incorporated into DNA and RNA
Azacytidine (Vidaza) & Decitabine (Dacogen) Elimination
Enzyme cytidine deaminase
deactivates Ara-C
Purine Antimetabolites Guanine Analogs
6-mercaptopurine (6-MP,Purinthol)
6-Thioguanine (6-TG)
Azothioprine (Imuran)
Purine Antimetabolites Adenosine Analogs
Pentostatin
Cladribine (2-cda, Leustatin)
Fludarabine (Fludara)
Guanine Analogs (6-MP, 6-TG) MOA and Uses
Converted to ribonucleotides that are incorporated into DNA
Inhibit purine synthesis

Uses: Leukemia
Guanine Analogs (6-MP, 6-TG)
Allopurinol increases 6-MP toxicity
6-MP is metabolized by xanthine oxidase
Allopurinol is a xanthine oxidase inhibitor
Adenosine Analogs Fludarabine Cladribine & Pentostatin Uses
lymphoma
Adenosine Analogs Fludarabine MOA
Inhibits DNA polymerase and ribonucleotide reductase,
incorporated into DNA
Cladribine & Pentostatin Adenosine Analogs MOA
Inhibits ribonucleotide reductase
Unlike fludarabine, these drugs are not deactivated by adenosine deaminase (cladribine inhibits AD)
Adenosine Analogs Fludarabine Cladribine & Pentostatin cause
DLT - myelosuppression (T cell depression)
Risk of opportunistic infections of PCP, HSV
*Recommend anti-infective prophylaxis*