CYTOTOXIC CHEMOTHERAPY 2014 -2015

Dr. Lim ONCOLOGY

4 types:  Platinum analog
1. conventional chemotherapy – doxorubicin, paclitaxel, docetaxel  For colon CA
2. Targeted agents – herceptin, bevacizumab, avastin
3. Hormonal therapies – tamoxifen S/E: prominently neurotoxic – most notorious
4. Biologic therapies – interferons, inteleukins
*it will not come out on the exam 
2. ANTITUMOR ANTIBIOTICS AND TOPOISOMERASE INHIBITORS
Review: Cell cycle
 DNA replication occurs during S phase MOA: They bind to DNA directly and can frequently undergo electron
 There are 5 phases (G0, G1, G2, S, M) transfer reactions to generate free radicals in close proximity to DNA
 The importance of cell cycle is that, different chemo drugs targets damage in the form of single strand breaks or cross links.
specific phases. They modify enzymes that regulate the capacity of DNA to unwind to
allow normal replication or transcriprion
CHEMOTHERAPEUTIC AGENTS USED FOR CANCER
Topoisomearse I – creates a single strand breaks that then rejoin
A. Phase non specific – agents which can act in any phase of the cell cycle following the passage of the other DNA strand through the break
B. Phase specific – agents which require the cell to be at a particular cell cycle
phase to cause greatest effect Toposiomerase II – creates a double strand breaks through which
*dose and side effects of the drugs will not be included in the exam, just another segment of DNA duplex passes before rejoining.
memorize the drugs under each classification DNA damage can occur in any cell cycle but cells tend to arrest In S Phase
(phase specific)
DIRECT DNA INTERACTING AGENTS
a. Doxorubicin
Formation of covalent DNA adducts:  Alter DNA structure, replication and topoisomerase II
 Powrerful vesicant with necrosis of tissue apparent 4-7 days after
1. ALKYLATING AGENTS (CELL CYCLE PHASE NON SPECIFIC) extravasation, should be administeresd into a rapidly flowing IV line
(NSS)
 Metabolized in the liver (careful with liver problems)
MOA: they break down either spontaneously or after normal organ or
tumor cell metabolism to reactive intermediate that covalently modify
S/E: acute cardiotoxicity, atrial and ventricular dysrhythmias
bases in DNA, this leads to cross linkage of DNA strands or appearance of
breaks in DNA as a result of repair efforts.
If >550 mg/m2 – causes chronic cardiotoxicity (cardiomyopathy)
S/E: alopecia, myelosuppression(bone marrow suppression), gonadal
b. Etoposide
dysfunction(sterility), mucositis, pulmonary fibrosis
 Prominent G2 phase arrest (phase specific)
Major toxicity: “second” neoplasm-leukemia
 Binds directly to topoisomerase II and DNA in a reversible ternary
a. Cyclophosphamide (non phase specific) complex
 Metabolized by 4-hydroxy-cyclophosphamide(active form) which  Given slowly, if it is too fast, can cause hypotension
decomposes into an alkylating species as well as chloroacetaldehyde
and acrolein. S/E: acute leukemia – “second” malignancy

Acrolein – causes chemical cystitis, if severe, cystitis can be treated by

MESNA and Hydration.

b. Ifosphamide (non phase specific)

 Cyclophosphamide analog also activated in the liver slowly
 Requires coadministration of mesna to prevent bladder injury INDIRECT EFFECTORS OF DNA FUNCTION
(cystitis)
1. ANTIMETABOLITES
S/E: CNS-confusion, somnolence, psychosis
MOA: cause DNA damage indirectly, by mis-incorporation into DNA,
Treatment: Mesna, hydration abnormal timing or progression through DNA synthesis or altered
function of pyrimidine and purine biosynthetic enzymes
c. Cisplatin Acts on S Phase (phase specific)
MOA: efficient bifunctional interactor with DNA forming DNA forming
cross links or breakage a. Methotrexate
 Requires administration of adequate hydration forced dieresis with  Inhibits dihydrofolate reductase which regenerates reduced folates
furosemide and mannitol to prevent kidney damage from the oxidized folates. Without reduced folates, cells die a
 Monitor creatinine level “thymine-less death”.
 Cleared by the kidney
C/I :patients with kidney problems  High dose of methotrexate with leukovorin is used for osteosarcoma
S/E: neurotoxicity, hearing loss, intensely emetogenic, myelosuppression,  Renal toxicity is augmented by renal dysfunction and drugs like
hypomagnesemia which can lead to hypocalcemia, Reynauds salicylates, probenecid, NSAIDs.
phenomenon (chronic vascular toxicity)  Sequestered in 3rd space(ascitis, effusion) collections causing
prolonged myelosuppression
d. Carboplatin  Can cause crystals in real tubules, so to prevent this, give sodium
 Less nephro-, oto- and neurotoxicity bicarbonate to alakalinize the urine

S/E: myelosuppression is more frequent

e. Oxiplatin

Et factum est ut amicis transcribit durum simul in unum!

Medicine vade
Page 1 of 3 yours truly, lj
 CYTOTOXIC CHEMOTHERAPY 2014 -2015
Dr. Lim ONCOLOGY
b. Pemetrexed c. Lapatinib
 Inhibits several enzymes including:  No action in cell cycle, sa EGF receptors lang siya
(These are enzymes used in purine and pyrimidine synthesis)  Used in Breast CA
 Thymidilate synthase
 Dihydrofolate reductase
 Glycinamide ribonucleotide formyltransferase
 Used in Lung CA and mesothelioma PROTEOSOME INHIBITOR “MIB”
a. Bortezomib
 Inhibitor of the proteosome
c. 5-Fluouracil (5FU)  Has activity in multiple myeloma and certain lymphomas
 Metabolized in cells to 5’FdUMP which inhibits thymidilate
synthetase S/E: neuropathy, orthostatic hypotension, w/ or w/o hyponatremia,
reversible thrombocytopenia

2. ANTIMITOTIC AGENTS
 M phase(phase specific)
HORMONAL AGENTS
a. Vincristine 1. Tamoxifen
 Binds to tubulin dimer with the result that microtubules are  10 fold greater antitumor activity in breast CA whose tumors express
disaggregated. estrogen receptors.
 Blocks M phase
 Causes peripheral neurotoxicity in the form of glove and stocking S/E: thromboembolic phenomena, endometrial CA (matagal ang gamit)
neuropathy

b. Vinblastine
 Similar to vincristine but more myelotoxic with more frequent
thrombocytopenia, mucositis, stomatitis.
c. TAXANES
 Blocks S phase
 Stabilize microtubules against depolymerization
 Microtubules function abnormally and are not able to undergo the
normal dynamic changes of microtubule structure and function
c.1 paclitaxel
 Requires use of Cremophor-containing vehicle that can cause
hypersensitivity reactions-premedicate with dexamethasone and
diphenhydramine
S/E: hypersensitivity reactions(patient turning violet),
myelosuppression, neurotoxicity, cardiac rhythm disturbances
c.2 docetaxel
 Requires polysorbate as a vehicle
 Cause fluid retention in addition to hypersensitivity reactions
 Give steroids and diuretics to prevent fluid retention
S/E: myelosuppression and neuropathy
2. Aromatase
 Family of enzymes that catalyze the formation of estrogen in various
tissues including ovary, and peripheral adipose tissue and some tumor
cells
 2 types of aromatase inhibitors:
a. Irreversible – steroid analogues such as exemestane
b. reversible – such as anastrozole, letrozole
3. Anastrozole
 Superior to tamoxifen in the adjuvant treatment of breast CA in
postmenopausal patients with estrogen receptor positive tumors.
*if premenopausal ang patient use tamoxifen
S/E: increase risk in osteoporosis (monitor bone mineral density)
LHRH (leutenizing hormone releasing hormone) agonist
Prostate CA – treated with androgen deprivation
Diethylstilbestrol (DES) – acting as an estrogen at the level of the
hypothalamus to downregulate LH.
Treatment:
1. Orchiectomy – equally effective as moderate-dose DES inducing
a response of 80% (best treatment) of previously untreated
patients with prostate CA but w/o the prominent cardiovascular
side effects of DES
*1st option orchiectomy, 2nd option leuprolide

2. Leuprolide and goserelin (LHRH agonist) – Tonic stimulation of

the LHRH receptor with the loss of its normal pulsatile activation
resulting in decreased output of LH in the anterior pituitary.
TYROSINE KINASE INHIBITORS “TINIB” *primary hormonal manipulation in prostate cancer, one can choose
 Acts on EGF receptors orchiectomy or leuprolide, but not both.

a. Imatinib
 Targets ATP binding site of the p210 protein tyrosine kinase that is
ANDROGEN RECEPTOR BLOCKER
formed as a result in chromosome 9,22 translocation producing CML
1. flutamide/ bicalutamide
*EGF antagonists – gefitinib, erlotinib, lapatinib  Uncertain additional benefit in extending overall response duration.

b. Gefitinib and erlotinib

 Used in lung CA (small cell)
 EGF antagonist that act at the ATP binding site of EGF receptor
tyrosine kinase

Et factum est ut amicis transcribit durum simul in unum!

Medicine vade
Page 2 of 3 yours truly, lj
 CYTOTOXIC CHEMOTHERAPY 2014 -2015
Dr. Lim ONCOLOGY
CLASSIFICATIONS OF DRUGS 6. Tyrosine kinase inhibitors
1. Alkylators “TINIBS”
 Cyclophosphamide  Imatinib
 Mechlorethamine  Gefitinib
 Chorambucil  Erlotinib
 Melphalan  Dasatinib
 Carmustine (BCNU)  Sorafenib
 Lomustine (CCNU)  Sunitinib
 Ifosphamide
 Procarbazine
 Dacarbizine (DTIC) 7. Protease inhibitors
 Temozolimide  Bortezomib
 Altretamine (formerly hexamethylmelamine)
 Cisplatin
 Carboplatin 8. Histone deacetylase inhibitors
 Oxaliplatin  Vorinostat
 Romidepsin

2. Antitumor antibiotics and topoisomerase poisons

 Bleomycin 9. mTor inhibitors
 Actinomycin D  Temsirolimus
 Etoposide  Everolimus’
 Topotetan
 Irinotecan
 Doxorubicin and Daunorubicin 10. Miscellaneous
 Idarubicin  Arsenic trioxide
 Epirubicin
 Mitoxantrone

3. Antimetabolites
 Deoxycoformycin
 6-mercaptopurine
 Azathioprine
 2-chlorodeoxyadeosine
 Hydroxyurea
 Methotrexate
 5 FU(5 fluouracil)
 Capecitabine
 Cytosine arabinoside
 Azacytidine
 Gemcitabine
 Fludarabine phosphate
 Asparaginase
 Premetexed

4. Antimitotic agents
 Vincristine
 Vinblastine
 Vinorelbine
 Paclitaxel
 Docetaxel
 Estramustine phosphate
 Nab-pacliatxel
 Ixabepilone

5. Molecularly targeted agents

A. Retinoids
o Tretinoin
o Bexarotene

B. targeted toxins
o Denileukin diftitox

Et factum est ut amicis transcribit durum simul in unum!

Medicine vade
Page 3 of 3 yours truly, lj