CANCER CHEMOTHERAPY PAUL DEXTER C.
SANTOS, MD, FPSP, FSMO
CANCER
 A disease characterized by an abnormal and uncontrolled proliferation of cells which can metastasize
or spread.
 Triggered by an interplay of genetic and environmental factors.
LECTURE NOTES: Neoplasia - is the uncontrolled
proliferation of cells; the difference between a
benign and malignant neoplasia is that the latter
can metastasize
The problem with cancer is: What symptom will
a 1 cm tumor give you? At 1 cm, the tumor is so
small and you already have a billion cancer cells
with the potential to spread. 1012 is already 1 kg
of cancer cells which can already overcome the
host, causing the death of the host.
The symptom depends on what organ the
nodule is.
LECTURE NOTES: 1 cm tumor found in the following organs. What are the symptoms?
 Lungs = few to nothing; because the lungs is a very large organ
 Brainstem = presence of neurologic symptoms; because the brainstem is a very compact organ
 Colon = few to nothing
 Breast = it depends on the size of the breast; if it’s big, you won’t be able to feel it; if it’s small,
you can spot the 1 cm nodule easily even from across the room you can see it.
 Tumor Doubling time (Td): the time it takes for a tumor to double its mass
 Solid tumors have longer Td’s compared to hematologic malignancies (2-3months vs 24hrs)
LECTURE NOTES: Why is it that blood malignancies and leukemia multiply faster than solid tumors?
It’s because solid tumors are limited by basement membrane and connective tissue surrounding it. So
the tumor has to do an extra effort to get its nutrients. Also, the basement membrane limits the spread
of malignancy. In contrast, in hematologic malignancies, there is no limit. The nutrients are already
there in the bloodstream hence, they have shorter doubling time and multiply faster.
 Therapy most effective in the stage where tumor burden is low, but growth rate is high
LECTURE NOTES: (refer to the graph before)
Low tumor burden and high growth rate should be typically observed before the limit of clinical
detection. But the problem is: It’s very hard to detect cancer when it’s size is lower than 1 cm. This is a
problem for cancer diagnosis and cancer treatment. If you catch them really early, sometimes it is not
enough to eradicate the entire cancer population.
First point (109 = 1 cm) in the graph represents the limit of detection of cancer cells which may be
asymptomatic depending on the location. Second point (1012= 1 kg) represents the stage where it is
irreversible and may lead to host death. In between the two points is where cancer growth is rapid and
where chemotherapy is applied. Once it reaches 1012 it will plateau because it will outgrow its blood
supply and the host will be deficient in nutrients; The bigger the tumor the lower the growth fraction
 World War I and II  Mustard Gas: Vesicant on skin, eyes, and respiratory tract; Induced leukopenia,
bone marrow aplasia, and dissolution of lymphoid tissue.
 Cytotoxic drugs: very narrow therapeutic window compared to other drugs
 A lot of cytotoxic drugs would entail giving a toxic dose for meaningful response to be achieved
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 TERMS

 Adjuvant chemotherapy: drug therapy given after a definitive treatment, (whether surgery or RT)
 Neoadjuvant chemotherapy: drug treatment given before a definitive treatment
 Metastatic setting: 1st line, 2nd line, 3rd line…etc
 Shifting from one regimen to another once with progression of disease

LECTURE NOTES: Adjuvant chemotherapy example: After breast surgery for breast cancer, you give
additional hormonal therapy.

Neoadjuvant chemotherapy example: The breast tumor is so big and you like to shrink it first to facilitate
the surgery.

For stage IV (those who are deemed to be incurable), in the metastatic setting, you start with one
regimen and if that already fails, you move on to a second line regimen and so on.
LECTURE NOTES: Toxic Dose = level at which you experience all the side effects

The problem is: With anti-cancer drugs, we have a very narrow therapeutic window. Meaning, the
effective dose of the drug is very much close to the toxic dose. So sometimes you really have to deal with CANCER TREATMENT AGENTS
the side effects. You really have to push the patient to the point of toxicity just for you to have a
meaningful response in treating a cancer.  Cytotoxic agents
 Alkylating agents, platinums, tumor antibiotics, anti-mitotic agents, anti-metabolites
 Hormonal treatment
 Biologic / Targeted Agents
 Anti-Estrogens, GnRH agonists, Androgen receptor blockers
 Binds to specific cell surface receptors or ligands
 Biologic response modifiers
 Intervenes with signal transduction
 Interleukin, G-CSF
 Targeted (biologic) agents
RECALL: Signal Transduction System is a way  Monoclonal antibodies
that outside signals are relayed to the nucleus  Tyrosine kinase inhibitors
to have an effect. In between the cell  Proteasome inhibitors
membrane and the nucleus, you have your  mTOR inhibitors
secondary messengers  Other protein kinase inhibitors
 Immune Check point inhibitors.

 Primary chemotherapy: drug therapy

administered as the primary treatment with
no alternative treatment (NHL, SCLCA, Wilm’s)
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 CYTOTOXIC AGENTS  Epipodophyllotoxins
- Etoposide
- Teniposide
ALKYLATING AGENTS  Anthracyclines
 Mechlorethamine Topoisomerase II Poison - Doxorubicin
 Cyclophosphamide - Epirubicin
Nitrogen Mustards - Daunorubicin
 Ifosfamide
 Melphalan - Idarubicin (Also classified as
 Chlorambucil tumor antibiotics)
 Hexamethylamine TUMOR ANTIBIOTICS PLATINUM COMPOUNDS
Ethylinimines and Methilinimines  Anthracyclines  Cisplatin
 Thiotepa
Alkyl Sulfonates  Busulfan  Mitomycin  Carboplatin
 Carmustine  Bleomycin  Oxaliplatin
Nitrosoureas  Lomustine  Dactinomycin
 Streptozocin MISCELLANEOUS
 Dacarbazine  Mitoxantrone
Triazines  Hydroxyurea
 Temozolomide
ANTIMETABOLITES  Procarbazine
Folic acid analogs  Methotrexate  Mitotane
 5-FU
Pyrimidine analogs  Floxuridine  CLASSIFICATION OF CYTOTOXIC AGENTS
 Cytarabine  Phase Non-specific
 Mercaptopurine o Alkylating Agents
 Thioguanine o Tumor antibiotics
Purine analogs
 Cladribine o Platinum Compounds
 Fludarabine  Phase Specific
ANTI-MITOTIC AGENTS o Cytarabine
 Vincristine o Hydroxyurea (interfere with DNA replication during S phase)
Vinca Alkaloids  Vinblastine o Methotrexate
 Vinorelbine
o 6-Mercap
 Paclitaxel
Taxanes o Vinca’s and Taxanes (interfere with M phase)
 Docetaxel
TOPOISOMERASE-INTERACTIVE AGENTS
REMEMBER: Antimetabolites are concerned with the DNA SYNTHESIS. Anti-mitotic agents are
 Camptothecins
concerned with CELL DIVISION.
Topoisomerase I Poison - Topotecan
- Irinotecan

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  Gonadal toxicity: germ cell depletion without damaging sertoli cells. Oligospermia,
aspermia, amenorrhea
 Pulmonary toxicity: busulfan, pneumonia like symptoms
 Alopecia
 Teratogenicity (15% risk of malformation if given in the first trimester)
 Carcinogenesis: acute leukemia in about 5%. More common in melphalan vs
cyclophosphamide
 Immunosuppression

LECTURE NOTES: TARGET CELLS: DNA; Once they produce damage in the DNA, the cells die through
apoptosis. There is resistance to chemotherapy drugs when the cell is not able to detect error (DNA
lesion) by the repair system

REMEMBER: The reason why you develop toxicities in the traditional chemotherapy agents: you kill
actively dividing cells (you also kill the NORMAL actively dividing cells seen in the hair, blood cells i.e.
WBCs, neutrophils, granulocytes, platelets, hemoglobin production, GIT, gonads).

Side effects of Alkylating agents affect cell division in normal cells.

LECTURE NOTES: Phase non-specific  can kill cancer cell at any point in the cell cycle; Phase specific 
active at certain stages of the cell cycle
NOTE: The ones in BOLD RED are important to remember.

• A.k.a. Mustargen
ALKYLATING AGENTS • The first, the original nitrogen mustard.
• Bifunctional alkylation
 Mechanism of action (MOA): • Given Intravenously
 Reacts with or ‘alkylates’ electron rich atoms in cells (electrophile characteristic) MECHLORETHAMINE • Rapidly undergoes transformation
 Forms covalent bonds with DNA components • Part of the primary MOPP regimen for Hodgkin’s Lymphoma
 Monofunctional: reacts with one strand of DNA (Mustargen, Vincristine/Oncovin, Prednisone, Procarbazine)
 Bifunctional: reacts with two strands of DNA forming a cross-link • Subcutaneous extravasation should be avoided as this may cause
severe necrosis
 Recognition of the DNA lesion by the repair system and lead to cell-cycle arrest and
• Presently, most widely used alkylating agent
eventually apoptosis.
• Bifunctional alkylates (two DNA strands)
 Induction of apoptosis is dependent on intact p53 system.
• Can be given IV or orally
 Toxicities: • Activated by Cyt P450, eventually generating phosphoramide
 Hematopoietic: Dose limiting toxicity CYCLOPHOSPHAMIDE
mustard and acrolein
- Affects granulocytes and platelets • 70% excreted in the urine
 Gastrointestinal toxicity: nausea and vomiting (less than the platinums) mediated via the • Phosphoramide mustard: anti-tumor effect
CNS • Acrolein: hemorrhagic cystitis (sudden onset of hematuria
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 combined with bladder pain and irritative bladder symptoms) ANTIMETABOLITES
• Fulminant cardiac toxicity at very high doses
• Wide range of application: Lymphomas (in CHOP regimen),
Leukemias, Breast cancer [adjuvant and primary metastatic],  Metabolite: Similar in structure with another substance but different enough to interfere with normal
autoimmune diseases) functions
** Rheumatologists also use this for lupus and in severe cases of  Methotrexate is the representative drug
rheumatoid arthritis.
REMEMBER: It breaks down into 2 molecules upon infusion  mustard and FOLIC ACID ANALOGS PURINE ANALOGS PYRIMIDINE ANALOGS
acrolein Methotrexate Mercaptopurine 5-Fluorouracil
• Monofunctional, so higher doses required Pemetrexed Thioguanine 5-FU prodrug: Capecitabine
• Used in sarcomas (soft tissue or osteogenic sarcomas) Fludarabine Cytarabine
IFOSFAMIDE Cladribine Gemcitabine
• Also produce hemorrhagic cystitis (so given together with mesna
that reacts with the acrolein).
• Alkylation at O6 guanine
*** PURINE ANALOGS
• CSF penetration: 15-30% of plasma concentration
• Carmustine (BCNU): for gliomas, brain tumors; multiple myeloma  Thioguanine and Mercaptopurine are good substrates for HGPRT converting them to ribonucleotides.
and high dose therapy in conjunction with BMT
 Incorporated into DNA which disrupts replication
• Local application of carmustine intra-operatively in biodegradable
NITROSOUREAS  Resistance:
polymers (wafers)
• Phenobarbital: increase clearance of BCNU (inducer of liver  Deficiency of HGPRT
microsomal enzyme).  Increased rates of degradation
REMEMBER: With nitrosoureas are CNS tumors. Because it’s one of the  Altered DNA-repair efficiency
drugs that is able to penetrate the CSF (BBB)
• Used in the ABVD regimen for Hodgkin’s Lymphoma (Doxorubicin, REMEMBER: When you hear ANTIMETABOLITES, just think of the base analogs (purine,
Bleomycin, Vinblastine, Dacarbazine). pyrimidine and folic acid analogs). These drugs are specific for the S phase.
• Generates active metabolite: MTIC: monomethyl
triazenoimidazole carboxamide
DACARBAZINE • Used in malignant melanoma • Inhibits DHFR enzyme
• ‘Flu-like’ syndrome of fever malaise, myalgias may occur after • Kills cells during S-phase
infusion. • Oral and IV administration (intrathecal : spinal or lumbar tap)
– Counteracted by Acetaminophen premedication • Triphasic elimination
– 1: distributive phase
• Orally administered analog of Dacarbazine – 2: renal excretion t1/2: 2-3 hours
METHOTREXATE
• Also generates MTIC – 3: renal excretion t1/2: 8-10 hours
• Penetrates BBB • Accumulation in 3rd spaces: ascites, pleural effusion  prolonged
TEMOZOLOMIDE exposure and increase in toxicity (just think of places where there
• Used in gliomas, as sole agent or in combination with radiation
therapy shouldn’t be any fluid or water)
REMEMBER: This is the second drug that will penetrate the BBB. • Toxicity: mainly bone marrow suppression
– Intrathecal: meningismus, seizures
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 – Teratogenesis, dermatitis, pneumonitis

PEMETREXED

REMEMBER: It inhibits 3 enzymes  Glycinamide ribonucleotide formyl

transferase (GARFT), Dihydrofolate reductase (DHFR), Thymidilate
synthase
• Clinical use: primary chemotherapy for:
– 1st line Metastatic Mesothelioma
• Clinical uses: – 1st line metastatic non-small cell lung cancer (with
– Childhood ALL primary induction of remission Cisplatin)
– Intrathecal prophylaxis in high grade lymphomas and – 2nd line Metastatic Non-small cell lung cancer
leukemias • Used together with vitamin B and folic acid supplementation to
– Choriocarcinoma limit toxicity
– High dose methotrexate • Inhibits Thymidilate Synthase enzyme
• Relapsed non-hodgkin’s lymphomas • Incorporated directly into DNA and RNA
• Osteosarcoma • Given intravenously
• Leukemias • Inactivated by Dihydropyrimidine Dehydrogenase enzyme (DPD) in
• Leucovorin given until methotrexate levels falls the liver
below 2 x 10-8 M • About 5% of the general population have inherited deficiency of
5-FLUOROURACIL
• Alkalinization of urine to facilitate excretion DPD, leading to severe toxicities
REMEMBER: Methotrexate, given at high doses, can cross the BBB. • Primary excretion: renal
• Toxicity:
• Bolus: myelosuppression
• Infusional: mucositis, GI side effects
• Modulator of effect: Leucovorin

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 • Co-factor that increases inhibition of TS
When 5-FU is incorporated in the DNA or RNA, the repair proteins come in
and recognize the faulty DNA and do the necessary shizzz.
• Clinical uses:
– Backbone in adjuvant and metastatic treatment of
colorectal and breast cancers
– Colorectal: combination with Leucovorin, Oxaliplatin, or
Irinotecan
– Breast: together with anthracyclines and alkylating agents;
adjuvant and metastatic
– Also beneficial in head & neck cancers, cervix, bladder,
prostate, pancreas and ovary.
• A prodrug of 5-FU
• Oral administration
MERCAPTOPURINE
• Converted to 5-FU through the enzyme thymidine phosphorylase
CAPECITABINE (TP)
• TP apparently has higher concentrations in tumor cells
• Usually taken daily for 14 days in a 3 week cycle
• Primary toxicity:
– Hand-foot syndrome (palmo-plantar erythrodysesthesia)
– Diarrhea/vomiting
REMEMBER: Analogy  5-FU: intravenous: capecitabine: oral
• Analog of 2-deoxycytidine
• Converted by deoxycytidine kinase to an active form:
5’monophosphate nucleotide
• Incorporated in DNA and inhibits DNA polymerase.
• Deactivated by cytidine deaminase
• Given IV (GIT has high levels of cytidine deaminase)
• Can be given intrathecally
• Toxicity:
CYTARABINE
– Myelosuppression: 3 cell lines: anemia, thrombocytopenia
and leukopenia
– GI disturbances, conjunctivitis
– Neurotoxicity/seizures after intrathecal.
• Clinical uses:
– Induction of remission in ALL (high dose: 2-3g/m2)
– Non hodgkins’ lymphomas
REMEMBER: This is the second drug that you can give intrathecally.
• Inhibits DNA polymerase, ribonucleotide reductase
• incorporates into DNA causing strand termination
• Also activated by deoxycytidine kinase
• Given IV
GEMCITABINE • Toxicity: myelosuppression (related with duration of infusion)
• Clinical use:
– First line in metastatic pancreatic cancer
– First line in metastatic NSCLCA (with platinum)
– Also in breast, cervix, ovarian cancer and sarcomas
• Analog of guanine
• Given orally but with variable absorption (5-37% bioavailability).
• Can be inactivated by:
– xanthine oxidase
– Thiopurine methyltransferase (in RBC)
• Major route of elimination: liver
• Clinical use:
– Induction of remission and maintenance in ALL
• Toxicity
- Myelosuppression (leuko and thrombocytopenia

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 • Adenosine analog motor weakness, constipation; Fatal if given intrathecally
• Inhibits DNA polymerase, ligase, primase, ribonucleotide  Vinblastine, Vinorelbine: Myelosuppression, leukopenia
reductase, incorporated into DNA and RNA nadir in 7-10 days
• Given intravenously  Hair loss
• Renal excretion  Extravasation causes severe necrosis
• Clinical use: • Clinical Indications:
– Chronic lymphocytic leukemia/ Small lymphocytic  Vinblastine:
FLUDARABINE
lymphoma - With Doxorubicin, Dacarbazine, Bleomycin (ABVD):
– Indolent NHL Hodgkin’s lymphoma
• Toxicities: myelosuppression, nausea, vomiting - With bleomycin, Cisplatin: testicular tumors
– Depletion in CD4 T cells - Kaposi’s sarcoma, neuroblastoma
REMEMBER: Depletion in CD4+ T cells  you will have opportunistic  Vincristine:
infections. It’s like having HIV infection. But this is reversible. If the drug - With Cyclo, Prednisone, Doxorubicin (CHOP): Non-
effect has already passed, the CD4+ T cell population will eventually recover. Hodgkin’s lymphoma
- With Mechlorethamine, Prednisone, Procarbazine
(MOPP): Hodgkin’s lymphoma
ANTI-MITOTIC AGENTS - Maximum single dose: 2mg
 Vinorelbine:
- With cisplatin: adjuvant and metastatic NSCLCA
VINCA ALKALOIDS TAXANES EPOTHILONES
• From the bark of yew tree.
Vincristine Paclitaxel Ixabepilone
• Promotes rather than inhibits microtubule formation (prevents
Vinblastine Docetaxel
microtubule destabilization)
Vinorelbine
• Cells arrest in metaphase
Vindesine
• Paclitaxel
– Delivered via Cremophor vehicle
REMEMBER: As a group of antimitotic agents, one common side effect is SENOSRINEUROPATHY – Increased incidence of allergic reactions and anaphylaxis
(numbness and tingling sensation in hands and feet). – Would need premedications with steroids and anti-
histamines
TAXANES – Metabolized by Cyt-P450 enzyme
• From Vinca rosea periwinkle plant
– Clearance altered by CytP450 inducers and inhibitors
• M-phase specific
• Paclitaxel Clinical use:
• Binds to tubulin causing dissolution of microtubules
– Breast cancer: Adjuvant, metastatic, in different
• Cell division arrests at metaphase
combinations with Doxorubicin and/or cyclophosphamide
• Mechanism of resistance:
VINCA ALKALOIDS – Lung cancer: with platinum agents cisplatin or carboplatin
– Increased P-glycoprotein expression (drug efflux pump)
for metastatic disease
– May be reversed by Ca channel blockers (verapamil)
– Ovarian cancer: with platinum agents for adjuvant or
• Hepatic clearance
metastatic disease
• Toxicities:
• Toxicity:
 Vincristine: neurotoxicity, numbness, tingling, loss of DTR,
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 – Primary toxicity: neutropenia, occuring 8-11 days.
– Neuropathy: glove-stocking sensory neuropathy
• Docetaxel
– 1.9-2x more potent than Paclitaxel (hence, more
pronounced neutropenia)
– Less allergic reactions
– More pronounced neutropenia than paclitaxel
– Clinical uses:
• Metastatic NSCLCA: singly or with platinum agents
• Adjuvant, neoadjuvant and metastatic Breast CA
• Head and neck cancers: with platinum and 5-
flurouracil
• Similar MOA with Taxanes:
• Ixabepilone:
– For metastatic breast cancer resistant to doxorubicin or
EPOTHILONES taxanes (regimen consists of Ixabepilone + Capecitabine)
– Non-cross resistance with taxanes
– More potent than taxanes
– Likewise metabolized in the liver by Cyt-P450
REMEMBER: VINCA ALKALOIDS VS TAXANES
Vinca alkaloids: you already have an existing microtubule that is already formed. The vinca
alkaloid will dissolve/destroy that. Hence, you prevent the metaphase from happening. It
prevents the elongation of the microtubules.
Taxanes: you already have an existing microtubule. Taxanes would prevent the dissolution or
the destabilization of the microtubules. The cell will be arrested at metaphase. The sister
chromatids will not divide because the taxanes are preventing the dissolution of the
microtubule. Taxanes prevent the shortening of the microtubules.
TOPOISOMERASE-INTERACTIVE AGENTS
 Topoisomerase: responsible for uncoiling or untangling DNA; Reduces chromosomal torsion in
supercoiled DNA that may interfere with cellular functions.
 Representative drug is Irinotecan.
TOPOISOMERASE I TOPOISOMERASE II
Epipodophyllotoxins: Etoposide, Teniposide
Camptothecins: Irinotecan, Topotecan Anti-tumor antibiotic: Anthracyclines (Doxorubicin,
Epirubicin)
Explanation of the picture: The topoisomerase is supposed to
move in accordance with the movement of the replication
fork. But if you have a drug (ex. Irinotecan), it will bind to
topoisomerase and will cause it to stop moving so that the
replication will not proceed. Later on, the cell will surely die
because it is unable to replicate the DNA.
• From Chinese Camptotheca acuminata
• Stabilize Topoisomerase I cleavable complex
• Mechanism of resistance:
CAMPTOTHECINS – P-glycoprotein drug efflux pump
– Decreased Topoisomerase I expression or affinity to DNA
– Exposure to Topo I agents leads to expression of Topo II
• Given Intravenously
• Converted to active metabolite: SN-38 by carboxylesterase
converting enzyme
• Major excretion pathway: glucuronidation by UGT1A1
– Patients with Criggler Najar or Gilbert’s syndrome are at
high risk of severe toxicity
• Clinical Uses:
CAMPTOTHECIN -
– Metastatic Colorectal cancers: with 5-FU, Leucovorin, or
IRINOTECAN
Capecitabine
– SCLCA, NSCLCA, cervical, ovarian, gastric cancer
REMEMBER: Irinotecan is excreted via glucoronidation pathway in the
liver. So that if you have patients with syndromes listed above, they have
high risk for toxicity and we do not give the irinotecan. You don’t use this in
patients with elevated bilirubin levels or those with biliary obstruction,
jaundice patients, and patients with bad liver.
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 • Toxicity: – Increased P-glycoprotein mediated efflux
– Acute diarrhea: cholinergic mediated, associated with • Common Toxicity:
abdominal cramps, salivation, diaphoresis, lacrimation; – Dose limiting: Cardiotoxicity
prevented by premedication with Atropine (anti- • Doxorubicin: > 450mg/m2 (1-10% incidence)
cholinergic) • Epirubicin: >900mg/m2
– Delayed diarrhea: probably SN-38 mediated, addressed • Presents as CHF
by loperamide • Acute cardiac toxicities: low voltage QRS,
– Neutropenia prolonged QT interval, sinus tachycardia
• From mandrake plant: Podophyllum peltatum – Cardiotoxicity due to Free radicals generated
• Stabilizes Topo-II cleavable complexes. • Heart has increased oxygen tension, rich
• Resistance mechanisms: mitochondria, and increased iron-containing
– Increased P-glycoprotein drug efflux myoglobin and hemoglobin
– P53 mutations that is essential for apoptosis • Epirubicin & Mitoxantrone: less cardiotoxic
– Decreased expression or mutation of topo-II – Severe extravasation reactions
• Etoposide: – Protect from light for prolonged infusion
– Oral and IV route – Neutropenia
– t1/2: 6-8 hours: renal clearance – Hair loss
– Conditions lowering albumin levels will lead to increased • Given intravenously. Bolus or infusional
EPIPODOPHYLLOTOXINS
free fraction, increasing toxicities • Infusional has higher rate of extravasation
– Therapeutic uses: • Multiphasic elimination: Liver
• With Cisplatin: Testicular cancers, SCLCA, • Clinical use:
NSCLCA – Doxorubicin: lymphomas, leukemias, breast cancer,
• Childhood ALL sarcomas, SCLCA
• Non-Hodgkin’s lymphoma – Daunorubicin: ALL and AML
– Toxicity: – Epirubicin: Breast cancer
• Leukopenia – Mitoxantrone (Anthracenedione): Acute non-lymphocytic
• Long term: Acute non-lymphocytic leukemia in leukemia, hormone-resistant prostate cancer.
children previously treated for ALL – Liposomal doxorubicin: less cardiotoxic, less neutropenia,
• Tumor antibiotic from Streptococcus species. used in ovarian cancer, lymphomas
• Several MOA’s
– Binds with Topo-II OTHER TUMOR ANTIBIOTICS
– Generate free radicals
– Intercalates DNA
ANTHRACYCLINES
– Promotes Apoptosis  Causes oxidative damage to DNA producing single and double
• Mechanisms of resistance strand breaks.
– Decreased activity of Topo-II – Administered IV, IM, intravesical.
BLEOMYCIN
– Increased glutathione peroxidase activity (lessens free – Renal exrection: t1/2 3hours
radical generation) – Clinical uses: germ cell tumors, HL and NHL.
– Toxicities:
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 • Pulmonary fibrosis (cummulative dose >250U); - Curative even in advanced germ cell tumors
supportive treatment  Toxicity:
• Initial sign is decline in CO2 diffusion capacity - Renal toxicity: tubular damage prevented by hydration
• Little myelosuppression and diuresis
• Cutaneous toxicity: hyperpigmentation, keratosis - Myelosuppression
 From Streptococcus caespitosus - Ototoxicity (high frequency hearing loss)
 Becomes an alkylating agent after intracellular enzymatic - Hypomagnasemia, hypokalemia, hypocalcemia
alterations - Most emetogenic chemotherapeutic drug
 Cross links at N6 of adenine and O6,N7 of guanine. (pinakanakakasuka)
 IV administration  Less reactive than cisplatin, better tolerated
 Elimination by chemical conjugation, and less than 10% excreted in  Less emetogenic, less nephro/neuro/ototoxicity
MITOMYCIN urine and bile  More pronounced neutropenia
 Clinical uses:  Half life: 2 hours
- Radiosensitizer for anal cancer  Dose computed as: (GFR+25) x AUC
- Cervix, stomach, breast, bladder (intravesical), lung, head CARBOPLATIN  Clinical uses:
and neck - Ovarian cancer, lung cancer, lymphomas, head and neck
 Toxicity: myelosuppression cancers, bladder cancer, germ cell tumors
• Most dangerous: HUS - Clinical trials demonstrate equivalence with cisplatin in
lung and ovarian cancers; inferior in head and neck and
PLATINUM COMPOUNDS germ cell tumors
 Produces more bulky adducts
 Least affected by MMR abnormalities
 Forms DNA ‘adducts’ (bulges in DNA structure) which are recognized by MMR (mismatch repair
 Long terminal half life (273 hours)
enzymes) and later leads to cell death
 Clinical uses:
 Forms intrastrand and interstrand cross-links. - GI cancers: Adjuvant and metastatic colorectal cancers;
 Enters cells by diffusion OXYPLATIN
Gastric cancers
 Resistance: - Ovarian, germ cell, cervical cancer.
- Defects or deficiencies in MMR  Toxicity:
- Increased activity of NER (nucleotide excision repair). - Dose limiting toxicity: Peripheral Neuropathy
- Not affected by P-glycoprotein - Less neutropenia

 A.k.a cis-diamminedichloroplatinum (CDDP) MISCELLANEOUS

 Given intravenously in normal saline solution
 Initial half life of 25-50 minutes, then terminal of 24 hours
CISPLATIN  Photosensitive  Enzyme from E. coli
 Clinical uses:  Deprives cancer cells of essential L-Asparagine blocking protein
L-ASPARAGINASE
- Germ cell tumors, Lung cancer, head and neck cancers, synthesis
ovarian cancer.  Component in regimens for ALL (Acute Lymphoblastic Leukemia)
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  Toxicity: • Valuable component in NHL, HL, CLL, ALL
- Hypersensitivity reactions (foreign protein) • MOA?- promote apoptosis (cytotoxic to your WBCs. That’s why
- Minimal BM and GI toxicity it’s used in combination with other chemotherapy agents such as
- Hyperglycemia, Hypoalbuminemia, protein C and S lymphomas.)
deficiency • Side effects:
- Pancreatitis (or severe abdomical pain) – Immunosuppression, glucose intolerance, osteoporosis,
 Inhibits enzyme ribonucleoside diphosphate reductase (converts water retention, GI ulcers
ribonucleotides to deoxy) • Most commonly used:
 Favors incorporation of other drugs (Cyta, Gemcitabine, – Letrozole
Fludarabine – Anastrozole
 Excellent oral bioavailability (80-100%) – Exemestane
 Crosses BBB • Inhibits aromatase enzyme that converts androgens to
 Urinary excretion estrogens
HYDROXYUREA  Clinical uses: - If you inhibit aromatase, you decrease the production
- Myeloproliferative diseases: polycythemia, CML, of your estrogen. This is beneficial to breast cancer
AROMATASE INHIBITORS
thrombocytosis patients who are positive to the estrogen receptor. So
- Sickle cell disease you test the tumor if it’s positive for the estrogen
 Toxicity: receptor so you can give aromatase inhibitors.
- Myelosuppression: leukopenia, thrombocytopenia, • Aromatase enzyme in adrenal glands and adipose tissue.
anemia • Indicated for post-menopausal ER/PR+ breast cancer patients
REMEMBER: This is the third drug that crosses the BBB in adjuvant, neoadjuvant, and metastatic setting.
• Side effect: decrease in bone mineral density, bone pains,
 Similar to DDT insecticide
increased fracture rates.
 Preferential attack of adrenal cortical cells
• binds to Estrogen Receptors preventing binding to DNA
 Orally administered
• Eventually decresaes autocrine stimulation of breast cancer
 Clinical use:
MITOTANE cells.
- Adrenocortical carcinoma (very rare)
• Has an agonist effect on endometrial cells and increases
 Toxicity:
thrombotic risk
- Anorexia, nausea
- Tamoxifen can have a stimulatory effect to endometrial
- Depletion of endogenous corticosteroids
cells. So that’s why when you give tamoxifen, you also
ANTI-ESTROGENS: TAMOXIFEN monitor once in a while with an ultrasound, the
HORMONAL AGENTS thickness of the endometrium. Sometimes it can get so
thick that it can develop into a cancer.
• Most commonly used: • Indicated in ER/PR+ pre or post-menopausal breast cancer
– Prednisone treatment (adjuvant or metastatic)
ADRENOCORTICOSTEROIDS – Dexamethasone • Side effect: thrombosis risk, endometrial CA, hot flashes,
• Able to induce remissions in hematologic cancers and nausea, vomiting, menstrual irregularities
responses in solid tumors REMEMBER: Tamoxifen directly binds to estrogen receptors while

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 aromatase inhibitors will just aim to lower the estrogen levels in your
body.
ANALOGY  Aromatase inhibitors side effects: Bone: Tamoxifen :
Blood vessels and endometrial cells
• More potent inhibitor of Estrogen Receptors
• Given in cases of failure with tamoxifen treatment.
• Down regulates the ER proteins
• Has no uterotrophic agonist activity (doesn’t stimulate
ANTI-ESTROGENS:
endometrial glands)
FULVESTRANT
• Given intramuscularly every month
NOTE: Both Tamoxifen and Aromatase inhibitors are given orally as
maintenance drugs that the patient takes for 10 years after breast
surgery.
• Prototypes: Goserelin, Leuprolide
• Administered intramuscularly or subcutaneously
• Initially stimulate FSH and LH production by the pituitary, then
later cause negative feedback inhibition.
• Estrogen levels fall to post-menopausal values (medical
GnRH ANALOGS
menopause/castration)
• Androgen levels fall to castrate values.
• Used in breast cancer and prostate cancer
• Can have initial ‘flare’ reaction which can be controlled by
concomitant anti-androgens or anti-estrogens
• Bicalutamide
• Flutamide
• Nilutamide
• Binds to Androgen receptors and causes complete androgen
ANTI-ANDROGENS blockade
• Usually given with GnRH analogs
• Side effects: decreased libido, hot flashes, gynecomastia,
mastodynia, paradoxical stimulation of androgen receptors (if
under anti-androgens for a very long time)
 Signal transduction: Relaying outside signals towards the nucleus causing specific gene expression
Explanation of the picture: GnRH will stimulate
the anterior pituitary. The anterior pituitary
will produce FSH and LH and then you’ll have
production of your hormones. What happens
when you give an exogenous GnRH analog? As
long as you are given the drug, you will
produce a permanent negative feedback. So
initially, you might have a flare with the end
products (testosterone or estrogen) but after
that, as long as you’re given the drug, you will
have a negative feedback. You, hence,
decrease the levels of testosterone and
estrogen. This is important also for estrogen
receptor positive breast cancer and for those
who have prostate cancer.
BIOLOGIC RESPONSE MODIFIERS
 Not directly cytotoxic
 Expands a T-cell response that is cytolytic for tumor cells
INTERLEUKIN-2
 Uses: Melanoma, Renal cell carcinoma, AML
 Toxicity: hypotension, peripheral edema, azotemia
 Filgrastim/ Lenograstim: expands population of neutrophil
G-CSF (GRANULOCYTE-
precursors (so you don’t get infections)
COLONY STIMULATING
 Prophylaxis for chemotherapy induced neutropenia
FACTOR)
 Side effects: fever, chills
NOTE: They do not directly kill the cancer cells.
TARGETED THERAPIES
and transcriptions of proteins promoting cell growth, proliferation, angiogenesis, etc.
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LECTURE NOTES: The underlined words are associated with cancer. You can interfere with transcription, CRIZOTINIB for c-Met and ALK dependent NSCLCA
cell growth, proliferation and angiogenesis so you can minimize or limit it because they are associated REGORAFENIB inhibits VEGFR for metastatic colon cancer
with cancer AFATINIB EGFR mutation in Non-small cell lung cancer
NOTE: Common side effects of first 6 drugs  rashes, asthenia, weakness

 Monoclonal antibodies (Mab’s): Target extracellular receptors or Ligands; they are large PROTEASOME INHIBITORS
immunoglobulins BORTEZOMIB Used in multiple myeloma; Adverse events mainly hematologic
 Tyrosine Kinase Inhibitors (TKI’s): Target intracellular receptor; Associated enzyme (tyrosine mTOR (mammalian target of Rapamycin) INHIBITORS
Kinases); they are small molecules mTOR A serine/threonine kinase involved in signal transduction
 Mab’s and TKI’s: used in Pancreatic neuroendocrine tumors, advanced Renal Cell
EVEROLIMUS
 Favorable side-effect profile (compared to traditional anti-neoplastic drugs) Cancer, Hormone receptor (+) breast cancer
 Cytostatic (drawback; not be able to kill but only prevent proliferation) TEMSIROLIMUS advanced Renal Cell Cancer
 Usually combined with cytotoxic agents

MONOCLONAL ANTIBODIES RECEPTOR SIDE EFFECTS LECTURE NOTE: If you inhibit mTOR, you prevent cell growth and proliferation.
Her2 receptor in breast cancer Congestive Heart Failure
TRASTUZUMAB (especially
 IMMUNE CHECKPOINT INHIBITORS
with anthracyclines)
 A.k.a. ‘Cancer Immunotherapy’
VEGF ligand to inhibit angiogenesis Hypertension,
BEVACIZUMAB - One of the proposed theories why cancer developed is that cancer is actually a
bleeding, proteinuria
EGFR receptor in colorectal and failure of the immune system. The cells of your immune system can no longer
CETUXIMAB skin rashes recognize that a particular cell/s is/are already abnormal.
head and neck cancers
PANITUMOMAB EGFR receptor in colorectal cancers  IMMUNE CHECKPOINT PROTEINS
RITUXIMAB CD20 receptor in B-cell lymphomas  Proteins present on surface of normal cells that gives an inhibitory signal to T-cells
PERTUZUMAB inhibits coupling of Her2  Protects the normal cells from T-cell attack
NOTE: Common to all  HYPERSENSITIVITY REACTIONS  Certain tumor cells ‘disguise’ themselves as ‘normal’ by bearing Immune Checkpoint
proteins (so they will not be attacked by T cells)
TYROSINE KINASE INHIBITORS RECEPTOR/TARGET  PD-1: Programmed cell Death protein -1
Bcr-Abl TKI in CML (Chronic myelogenous leukemia); CD117 TKI in - Found on surface of T-cells
IMATINIB (GLEEVEC)
GIST (Gastrointestinal stromal tumors) - Inhibited by: Nivolumab and Pembrolizumab
GEFITINIB EGFR TKI in NSCLCA (Non-small cell lung cancer)  PD-L1: Programmed cell Death Ligand -1
ERLOTINIB EGFR TKI in NSCLCA and pancreatic cancer
- Found on surface of cancer cells, mimicking normal cells
SUNITINIB Multikinase; in Renal and Liver cancer
- Inhibited by: Atezolizumab
SORAFENIB Multikinase; in Renal and Liver cancer
LAPATINIB EGFR and Her2 TKI in breast and head and neck CA
(multikinase inhibitor) VEGF-R, PDGFR, c-kit (metastatic renal cell
AXITINIB AND PAZOPANIB
cancer)
VEMURAFENIB for malignant melanoma bearing mutations in B-Raf enzyme
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LECTURE NOTES: The left picture shows the MOA of Mab’s and TKI’s. The right picture shows a
Mab structure. Let’s say the lower right picture is Bevacizumab binding to VEGF ligand. The
tumor (cancer cell/nodule) can sustain itself. It can nourish itself from its surroundings up until
just 1 cm in size. However, if it must expand, then it has to make its own network of blood
vessels. And the tumor does that by the VEGF pathway. The aim of this drug is to prevent the
neoangiogenesis going on so that it will limit the size of the tumor and limit the spread.
NOTE: Proteasome = “garbage bin” of the cell; The proteasome degrades ageing proteins and you know that
the molecules are ageing because these molecules are ubiquinated.
LECTURE NOTES: This is the logic behind ‘cancer immunotherapy’.
Left picture: Once the PD-1 of the T cell recognizes the PD-L1 of the tumor cell, it will “label”
the tumor cell: This cell is not to be touched.
Right picture: If you block PD-1 and PD-L1, this is the time that the T cell will destroy the tumor
cell.
 MOLECULAR PROFILING
 It tells you what genes are present, what proteins are overexpressed in the cancer cells.
Based on these information, you give the appropriate targeting drug.

LECTURE NOTES:

Proteasome inhibitors would actually

block the entrance of your proteasome.
Once Ikb is degraded, it will release the
NFKb which is a transcription factor that
will cause cell proliferation, cell survival,
and angiogenesis. So if you prevent
degradation of Ikb, it will not release
NFKb.

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 ORGAN TEST DRUG TREATMENT  Mechlorethamine + Dacarbazine? No. Both are alkylating agents. But sometimes, they are
 Trastuzumab combined.
BREAST Her2Neu testing  Lapatinib,  Etoposide + Cisplatin? Yes. Different MOAs. Etoposide is hepatic while Cisplatin is renal.
 Pertuzumab  Paclitaxel + Carboplatin + Bevacizumab? Yes. Bevacizumab will not have the same side effect
 Gefitinib profile.
LUNGS EGFR testing  Afatinib,  Irinotecan + Cetuximab? Yes. One is a cytotoxic drug and the other one is a biologic agent
 Erlotinib (colon cancer)
ALK testing  Crizotinib  Bevacizumab + Erlotinib? Yes. Both are biologic agents because they have different side
COLON EGFR T90M mutation  Osimertinib effect profile
 Cetuximab
LYMPHOMA Kras testing
 Panitumamab
 Self-check:
 Imatinib
GIST/CML cKIT, BcR-Abl testing  What are the 3 drugs that can cross the BBB?
 Dasatinib
 What are the two drugs that are given intrathecally?

MNEMONICS:
COMBINATION CHEMOTHERAPY
Platinums: COC planet (cisplatin,
 Provides maximal cell kill; Prevent or slow the subsequent development of drug resistance oxaliplatin, carboplatin)
 Broader range of interaction between the drugs with different MOA’s and the heterogenous tumor Anti-androgen: Bro Find Nemo
(bicalutamide,
 Combination chemotherapy: Usually Traditional and new biologic agents.
flutamide, nilutamide)
 Drugs can be combined if: Anti-mitotic agents: Si VIN ay TAXEL
 Each drug is effective as a single agent (VINca alkaloids,
 Drugs that cause complete remission are preferred TAXanes,
 If drugs equally effective, choose the ones with less or non-overlapping toxicities PacliTAXEL,
 Drugs should not affect each other’s PK DoceTAXEL,
 Cytotoxics (traditional agents) and Biologics (targeted agents) Epithilones)
mga ex ni VIN: vinCRISTINE,
LECTURE NOTES: You combine drugs with different MOAs because you’re trying hit the tumor and it’s vinBLASTINE,
believed that the cancer tumor is heterogeneous. It’s not just one type of cell so with different MOAs, vinORELBINE,
you can get different cells inside the tumor. You combine it. vinDESINE
Penetrates the BBB: No to
Hamburgers BaByBoo
 COMBINE…? (Nitrosoureas,
 Oxaliplatin + Vincristine? No. Both are neurotoxic. Temozolomide, Hydroxyurea)
 Paclitaxel + Carboplatin? Yes. Paclitaxel is disposed in the liver while carboplatin is disposed BaByBoo: blood brain barrier
in the kidneys. Different MOAs.

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 END OF TRANSCRIPTION

Day by day, dear Lord,

Let me touch many lives for You.
By Your Spirit,
Quicken every life
By the words I speak, the prayers I breathe, or the life I live
And all for Jesus sake. Amen.

Transcription Team
2019
Transcribed by: Phoebe Grande
Edited by: Louise Beltran
References: Doc Dex’s .ppt
Lecture notes and recording
Remarks: Sorry if it’s lengthy but I tried including
all the infos. I did not include the parts
in the past trans that Doc Dex did not
discuss. Just memorize by heart those in
bold red because he emphasized it.

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