CANCER CHEMOTHERAPY 2

Dr. Paul Dexter C. Santos

TABLE OF CONTENTS

I. Cancer Treatment Agents

A. Cytotoxic Agents
1. Alkylating Agents
2. Anti-metabolites
3. Anti-mitotic Agents
4. Topoisomerase-interactive Agents
5. Other tumor antibiotics
6. Platinum compounds
7. Miscellaneous
B. Hormonal Treatment
1. Adrenocorticosteroids
2. Aromatase Inhibitors
3. Anti-estrogens
4. GnRH Analogs
5. Anti-androgens
C. Biologic Response Modifiers
1. Interleukin-2
2. G-CSF Figure 1: Logarithmic growth of cancer cells
D. Targeted (Biologic) Agents
1. Monoclonal Antibodies ● The first point in the graph (109=1 cm) represents the limit of detection of
2. Tyrosine Kinase Inhibitors
3. Proteasome Inhibitors
cancer cells which may be asymptomatic depending on the location.
4. mTOR Inhibitors Anything less than this is undetectable.
5. Immune Checkpoint Inhibitors ● What symptom will a 1 cm tumor give you?
6. Molecular Profiling ○ Lungs, Liver, Colon: nothing
E. Combination Chemotherapy
○ Brainstem: neurologic symptom since it is a small organ
○ Breast: depends on the size of the breast; if it’s big, you won’t
even feel it; if it’s small, it can be easily seen
CANCER
● The second point in the graph (1012=1 kg) represents the stage where it is
● A disease characterized by an abnormal and uncontrolled proliferation of
irreversible. 1 kg of cancer cell is too much for the body to handle and may
cells which can metastasize or spread
lead to the death of the host.
● Triggered by an interplay of genetic and environmental factors (e.g family
Growth of cancer cell as you can see in the graph is rapid then goes into a plateau
history, smoking, and pollution)
once it exhaust the blood supply and host will be deficient of nutrient
Notes:
● Neoplasia - is the uncontrolled proliferation of cells
○ Benign neoplasia: stays at one place; encapsulated; in situ
○ Malignant neoplasia: ability to metastasize

Cancer Chemotherapy (Dr. Paul C. Dexter Santos)

September 27, 2017
Note:
✓ The ones in BOLD RED are important to remember.
● Tumor Doubling time (Td): The time it takes for a tumor to double its mass
○ Solid tumors have longer Td’s (2-3 months) vs hematologic
malignancies (24 hours)
○ Hematologic malignancies (leukemia, etc.) multiply faster because
of the presence of basement membrane, lamina propia and blood
supply that somehow limits the solid tumors.
● Therapy is most effective in the stage where tumor burden is low, but
growth rate is high. However, this is the stage before the limit of detection
where in the cancer is still undetectable. (Doc Dex: that is the problem with
cancer. The time where it is most effective to treat is where it is
undetectable clinically)
● Source of the drug: During World War I and II → Mustard Gas : Vesicant
on skin, eyes, and respiratory tract; induced leukopenia, bone marrow
aplasia, and dissolution of lymphoid tissue.
Figure 2. In between 2 points is the margin of safety(therapeutic window).
● Cytotoxic Drugs: very narrow therapeutic window and would entail giving
or pushing to a toxic dose for a meaningful response. (That’s why there are
lots of side effects in anti-cancer drugs. Going too mild would mean no side
effect but no primary effect also)
CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
Figure 3. Biologic Agents
● Biologic/Targeted Agents
○ Binds to specific cell surface receptors or ligands
○ Intervened with signal transduction
○ Lesser adverse effect compared to traditional chemotherapeutic
drugs
TERMS
● Primary chemotherapy: Drug therapy administered as the primary
treatment with no alternative treatment (NHL, Small Cell Lung Cancer,
Wilm’s Tumor); (Best treatment -Doc Dex)
● Adjuvant chemotherapy: Drug therapy given after a definitive treatment
(like mastectomy in breast CA), add on chemotherapy for elimination of
microscopic cancer cells
● Neoadjuvant chemotherapy: Drug treatment given before a definitive
treatment (like in cases of massive tumors, you need to shrink the tumor
first to make it manageable for the surgeon to remove)
● Metastatic setting: 1st line, 2nd line, 3rd line… etc
○ Shifting from 1 chemotherapy regimen to another once the
disease progresses
● Targeted therapy: modern biologic agents like monoclonal antibodies and
tyrosine-kinase inhibitors, etc.
Notes:
Adjuvant chemotherapy example: After breast surgery for breast cancer, you
give additional hormonal therapy.
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 Neoadjuvant chemotherapy example: The breast tumor is so big and you like Notes:
to shrink it first to facilitate the surgery. JUST FAMILIARIZE YOURSELF WITH THE NAMES -Doc Dex

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 Alkylating agents:
line regimen and so on. ○ Nitrogen Mustard: Mechlorethamine,
Cyclophosphamidephamide, Ifosfamide, Melphalan, Chlorambucil
○ Ethylinimines and Methilinimines: Hexamethylamine, Thiotepa
CANCER TREATMENT AGENTS ○ Alkyl Sulfonates: Busulfan
● Cytotoxic agents ○ Nitrosoureas: Carmustine, Lomustine, Streptozocin
○ Alkylating agents, platinums, tumor antibiotics, anti-mitotic ( for ○ Triazines: Dacarbazine, Temozolomide
CELL DIVISION) agents, anti-metabolites (for DNA SYNTHESIS) ● Antimetabolites: active during DNA Synthesis
● Hormonal treatment ○ Folic acid analogs: Methotrexate
○ Anti-Estrogen, GnRH agonist, Androgen receptor blockers (drugs ○ Pyrimidine analogs: 5-FU, Flozuridine. Cytarabine
for breast and prostate cancer) ○ Purine analogs: Mercaptourine, Thioguanine, Cladribine,
● Biologic response modifiers Fludarabine
○ Interleukin, G-CSF ● Anti-mitotic agents: active during mitosis stage
● Targeted (biologic) agents ○ Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine
○ Monoclonal antibodies ○ Taxanes: PAclitaxel, Decetaxel
○ Tyrosine kinase inhibitors ● Topoisomerase-interactive agents: intefere with replication
○ Proteasome inhibitors ○ Topoisomerase I poison: Camptothecins, Topotecan, Irinotecan
○ mTOR inhibitors ○ Topoisomerase II poison:
○ Other protein kinase inhibitors ■ Epipodophyllotoxins: Etoposide, Teniposide
○ Immune checkpoint inhibitors ■ Anthracyclines: Doxorubicin, Epirubicin, Daunorubicin,
Idarubicin (Also classified as tumor antibiotics)
CYTOTOXIC AGENTS ● Tumor antibiotics:
○ Anthracyclines
● CLASSIFICATION OF CYTOTOXIC AGENTS ○ Mitomycin
○ Phase Non-specific (kills cancer at any point) ○ Bleomycin
■ Alkylating agents ○ Dactinomycin
■ Tumor antibiotics ● Platinum compounds:
■ Platinum Compounds ○ Cisplatin
○ Phase specific (acts on certain stages of the cell cycle) ○ Carboplatin
■ Cytarabine ○ Oxaliplatin
■ Hydroxyurea (interferes S-Phase) ● Miscellaneous:
■ Methotrexate ○ Mitoxantrone
■ 6-Mercap ○ Hydroxyurea
■ Vinca’s and Taxanes (interferes M-phase) ○ Procarbazine
○ Mitotane

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CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
 Notes: Patient’s fertility may be temporarily affected after therapy.
Chemotherapeutic drugs cannot differentiate between cancer cells and normal cells

Both are actively dividing thus, both are killed by the agent.

○ Examples:
● Alopecia (hair loss):
○ mistakenly attacks hair follicles
● Gastrointestinal toxicity:
○ nausea and vomiting (less than the platinums) mediated
Notes: Phase non-specific can kill cancer cell at any point in the cell cycle; via the CNS,
Phase specific active at certain stages of the cell cycle ○ diarrhea
● Blood disorders
○ Anemia, Leukopenia, Thrombocytopenia
ALKYLATING AGENTS ● Gonadal toxicity
○ germ cell depletion without damaging sertoli cells.
● Reacts with or ‘alkylates’ electron rich atoms in cells (electrophile ○ Oligospermia, aspermia, amenorrhea
characteristic) ● Pulmonary toxicity
● Forms covalent bonds with DNA components ○ busulfan, pneumonia like symptoms
● Monofunctional: reacts with one strand of DNA ● Teratogenicity
● Bifunctional: reacts with two strands of DNA forming a cross-link ○ 15% risk of malformation if given in the first trimester
● Mechanism of action (MOA): ● Increased risk of future malignancies
a. Distortion of DNA ○ Carcinogenesis: acute leukemia in about 5%.
b. Recognition of the DNA lesion by the repair system ○ More common in Melphalan Vs. Cyclophosphamide
c. Cell-cycle arrest Notes:
d. Apoptosis - dependent on intact p53 system ✓ Just familiarize yourself with the clinical uses. Don’t memorize.
Notes: ✓ The ones in BOLD RED are important to remember.
p53
○ labeled as the “Guardian of the Genome”
○ Sounds the alarm to kill cells with DNA damage so that it won’t
replicate and prevent them from being cancerous ALKYLATING AGENT DESCRIPTION

MECHLORETHAMINE - A.k.a. Mustargen

● Toxicities (Nitrogen mustard) - The first, the “Original Nitrogen Mustard”
○ Hematopoietic: Dose limiting toxicity - Bifunctional alkylation
■ Affects granulocytes and platelets - Given Intravenously
- Rapidly undergoes transformation
○ Immunosuppression
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 - Part of the primary MOPP regimen for Hodgkin’s liver microsomal enzyme).
Lymphoma (Mustargen, Vincristine/Oncovin,
Prednisone, Procarbazine) DACARBAZINE - Used in the ABVD regimen for Hodgkin’s Lymphoma
- Subcutaneous extravasation should be avoided as this (Triazine) (Doxorubicin, Bleomycin, Vinblastine, Dacarbazine).
may cause severe necrosis (veins should be intact - Generates active metabolite: MTIC: monomethyl
because it is cytotoxic) triazenoimidazole carboxamide
- Used in malignant melanoma
CYCLOPHOSPHAMIDE - Presently, most widely used alkylating agent - ‘Flu-like’ syndrome of fever malaise, myalgias may occur
(Nitrogen mustard) - almost the same with Ifofsamide after infusion.
- Bifunctional alkylates (two DNA strands) - Counteracted by Acetaminophen premedication
- Can be given IV or orally
- Activated by Cyt P450, eventually generating TEMOZOLAMIDE - Orally administered analog of Dacarbazine
phosphoramide mustard and acrolein (Triazine) - Also generates MTIC
- 70% excreted in the urine - Used in gliomas (like Nitrosoureas), as sole agent or in
- Phosphoramide mustard: anti-tumor effect combination with radiation therapy
- Metabolite: Acrolein - Second drug that will penetrate the BBB.
- causes Hemorrhagic cystitis
- sudden onset of hematuria combined with
bladder pain and irritative bladder symptoms ANTI-METABOLITES
- Fulminant cardiac toxicity at very high doses ● Not really “anti” but are analogs of components of DNA synthesis
- Wide range of application: Lymphomas (in CHOP ● Analog: similar in structure with another substance but different enough
regimen), Leukemias, Breast cancer [adjuvant and to interfere with normal functions
primary metastatic], autoimmune diseases) ● Base analogs: Purine, Pyrimidine, and Folic acid analogs
● Specific for the S phase
IFOFSAMIDE - still widely used today
● Representative drug: Methotrexate
(Nitrogen mustard) - Monofunctional, so higher doses required
● Purine Analogs:
- Used in sarcomas (soft tissue or osteogenic sarcomas)
- Also produce hemorrhagic cystititis (given together ○ Thioguanine and Mercaptopurine are good substrates for HGPRT
with mesna (ANTIDOTE) that reacts with acrolein) converting them to ribonucleotides.
○ Incorporated into DNA which disrupts replication
NITROSOUREAS - Alkylation at O6 guanine ○ Resistance: Deficiency of HGPRT, increased rates of degradation ,
- CSF penetration (BBB): 15-30% of plasma altered DNA-repair efficiency
concentration
- all drugs ending in ‘stine’ (carmustine, lomustine,
semustine) for brain gliomas FOLIC ACID ANALOGS PURINE ANALOGS PYRIMIDINE ANALOGS
- (when you hear the word, “Nitrosoureas”, the first thing
that comes to mind is “CNS”) Methotrexate Mercaptopurine 5-Fluorouracil
- Carmustine (BCNU): for gliomas, brain tumors; multiple Pemetrexed Thioguanine 5-FU prodrug: Capecitabine
myeloma and high dose therapy in conjunction with Fludarabine Cytarabine
BMT Cladribine Gemcitabine
- Local application of carmustine intra-operatively in
biodegradable polymers (wafers)
- Phenobarbital: increase clearance of BCNU (inducer of

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 ANTI-METABOLITE DESCRIPTION - Relapsed non-hodgkin’s lymphomas
- Osteosarcoma
METHOTREXATE - still widely used today - Leukemias
(Folic - representative drug - Leucovorin given until methotrexate levels
acid analog) - Inhibits Dihydrofolate reductase (DHFR) enzyme falls below 2 x 10-8 M
- Alkalinization of urine to facilitate excretion
- can cross the BBB

PEMETREXED
(Folic acid analog)

- Oral and IV administration (intrathecal : spinal or lumbar - Toxicity: Severe anemia

tap)
- Accumulation in 3rd spaces:
- parts of the body that should not contain any or
minimal amount of water pleural fluid, peritoneal
fluid)
- It should be a continuous cycle of production and
drainage
- results to ascites or pleural effusion
- Terminal half life is extended when patients with ascites
or pleural effusion is given with methotrexate
- Increase in toxicity: myelosuppression
- given intrathecally (spine first then spread to CSF):
meningismus, seizures
- Teratogenesis, dermatitis, pneumonitis
Clinical uses:
1. Childhood ALL primary induction of remission
2. Intrathecal prophylaxis in high grade lymphomas and
leukemias
3. Choriocarcinoma
4. High dose methotrexate
- Used together with vitamin B and folic acid
supplementation to limit toxicity
- It inhibits 3 enzymes:
1. Glycinamide ribonucleotide formyl transferase
(GARFT)
2. Dihydrofolate reductase (DHFR)
3. Thymidilate synthase
Clinical use:
- Primary chemotherapy for:
- 1st line Metastatic Mesothelioma
- 1st line metastatic non-small cell lung cancer (with
Cisplatin)
- 2nd line Metastatic Non-small cell lung cancer
5-FLUOROURACIL - Representative drug for pyrimidine analogs
(5-FU) - Inhibits Thymidilate Synthase enzyme
(Pyrimidine analog) - Incorporated directly into DNA and RNA
- Given intravenously
- Inactivated by Dihydropyrimidine Dehydrogenase enzyme
(DPD) in the liver
- About 5% of the general population have inherited

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CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
 deficiency of DPD, leading to severe toxicities - Deactivated by cytidine deaminase
- DPD is supposed to deactivate 5-FU - Given IV (GIT has high levels of cytidine deaminase)
- Given with modulator: Leucovorin - 2nd drug that can be given intrathecally (first is
- Primary excretion: renal methotrexate)

Toxicity:
- Bolus: myelosuppression
- Infusional: mucositis, GI side effects
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.
CAPECITABINE - Also beneficial in head & neck cancers, cervix, bladder,
(Pyrimidine analog) prostate, pancreas and ovary.
- Oral form
- Prodrug of 5-FU (5-FU is given intravenously)
- Converted to 5-FU through the enzyme thymidine
phosphorylase (TP)
- TP apparently has higher concentrations in tumor cells
- Usually taken daily for 14 days in a 3 week cycle
- Primary toxicity:
1. Hand-foot syndrome (palmo-plantar
erythrodysesthesia)
- reddish or black hands; sometimes painful
- decrease the dose or shift to another drug
2. Diarrhea/vomiting
Important!! Discuss everything with your patients (esp side
effects of drugs). Never assume that these side effects are
nothing. Because it might mean nothing to you, but it might
mean the whole world for your patient.
Toxicity:
1. Myelosuppression: 3 cell lines: anemia,
thrombocytopenia and leukopenia
2. GI disturbances, conjunctivitis
3. Neurotoxicity/seizures after intrathecal.
Clinical uses:
1. Induction of remission in ALL (high dose: 2-3g/m2)
2. Non hodgkins’ lymphomas
GEMCITABINE - Inhibits DNA polymerase, ribonucleotide reductase
(Pyrimidine analog) - incorporates into DNA causing strand termination
- Also activated by deoxycytidine kinase
- Given IV
- Toxicity: myelosuppression (related with duration of
infusion)
Clinical use:
1. First line in metastatic pancreatic cancer
2. First line in metastatic NSCLCA (with platinum)
3. Also in breast, cervix, ovarian cancer and sarcomas
MERCAPTOPURINE - Analog of guanine
(Purine analog) - Given orally but with variable absorption (5-37%
bioavailability).
- Can be inactivated by:
a. Xanthine oxidase
b. Thiopurine methyltransferase (in RBC)
- Major route of elimination: liver
Clinical use: Induction of remission and maintenance in ALL
Toxicity: Myelosuppression (leuko and thrombocytopenia

CYTARABINE - Analog of 2-deoxycytidine FLUDARABINE “Cytotoxic drugs, in general, affect neutrophils causing
(Pyrimidine analog) - Converted by deoxycytidine kinase to an active form: (Purine analog) Neutropenia, predisposing the patient to bacterial infections.”
5’monophosphate nucleotide - Adenosine analog
- Incorporated in DNA and inhibits DNA polymerase. - Depletion in CD4+ T cells

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DR. PAUL DEXTER C. SANTOS
 - presence of opportunistic infections like Pneumocystis
● Hepatic clearance
pneumonia ● Toxicities:
- just like having HIV infections but reversible ○ Hair loss
- if the drug effect has already passed, the CD4+ T cell ○ Extravasation causes severe necrosis
population will recover
- treatment: prophylactic antibiotics
- Inhibits DNA polymerase, ligase, primase, ribonucleotide VINCA TOXICITIES CLINICAL INDICATION
reductase, incorporated into DNA and RNA ALKALOIDS
- Given intravenously
- Renal excretion - With Cyclo, Prednisone, Doxorubicin
Fatal if given (CHOP): Non Hodgkin’s lymphoma
Clinical use: intrathecally - With Mechlorethamine, Prednisone,
1. Chronic lymphocytic leukemia/ Small lymphocytic VINCRISTINE neurotoxicity,
Procarbazine (MOPP): Hodgkin’s
lymphoma numbness, tingling, loss
of DTR, motor weakness, lymphoma
2. Indolent NHL
constipation - Maximum single dose: 2mg
Toxicities:
- Myelosuppression
- Nausea - With Doxorubicin, Dacarbazine,
- Vomiting Bleomycin (ABVD): Hodgkin’s lymphoma
Myelosuppression, - With bleomycin, Cisplatin: testicular
VINBLASTINE
ANTI-MITOTIC AGENTS leukopenia nadir in 7-10 tumors
● Acts/interferes during Mitotic phase of cell division days - Kaposi’s sarcoma, neuroblastoma

VINORELBINE - With cisplatin: adjuvant and metastatic

VINCA ALKALOIDS TAXANES EPOTHILONES NSCLCA
Vincristine Paclitaxel Ixabelipone
Vinblastine Docetaxel TAXANE
Vinorelbine
Vindesine ● From the bark of yew tree
● Promotes rather than inhibits microtubule formation
○ prevents microtubule destabilization
VINCA ALKALOIDS
● From Vinca rosea periwinkle plant ○ Remember!! Microtubule has to be dissolved to pull sister
● M-phase specific chromatids apart. Taxanes prevent this separation
● Binds to tubulin causing dissolution of microtubules ● Cells arrest in metaphase
● Cell division arrests at metaphase
● Be careful administering this, it is highly vesicant
○ Vesicant - agent that induces blistering PACLITAXEL - Delivered via Cremophor vehicle (used to dissolve it)
● Mechanism of resistance: - Increased incidence of severe allergic reactions and
○ Increased P-glycoprotein expression (drug efflux pump) anaphylaxis
○ May be reversed by Ca channel blockers (verapamil)
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CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
 - Would need premedications with steroids and anti-
histamines
- Metabolized by Cyt-P450 enzyme
- Clearance altered by CytP450 inducers and inhibitors
Clinical use:
- Breast cancer: Adjuvant, metastatic, in different
combinations with Doxorubicin and/or
cyclophosphamide
- Lung cancer: with platinum agents cisplatin or
carboplatin for metastatic disease
- Ovarian cancer: with platinum agents for adjuvant or
metastatic disease
Toxicity:
- Primary toxicity: neutropenia, occurring 8-11 days.
- Neuropathy: glove-stocking sensory neuropathy
DOCETAXEL - 1.9-2x more potent than Paclitaxel (hence, more
pronounced neutropenia)
- More pronounced neutropenia than paclitaxel
- Less allergic reactions
Clinical use:
- Metastatic NSCLCA: singly or with platinum agent
- Adjuvant, neoadjuvant and metastatic Breast CA
- Head and neck cancers: with platinum and 5-flurouracil
EPOTHILONES - Similar MOA with Taxanes:
- IXABEPILONE:
○ For metastatic breast cancer resistant to doxorubicin
or taxanes (regimen consists of Ixabepilone +
Capecitabine)
○ Non-cross resistance with taxanes
○ More potent than taxanes
○ Likewise metabolized in the liver by Cyt-P450
CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
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
● Agents that interfere with DNA replication
● 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,
Camptothecins: Irinotecan, Topotecan Teniposide
Anti-tumor antibiotic: Anthracyclines
(Doxorubicin, Epirubicin)
Figure 4. 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.
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 - Increased P-glycoprotein drug efflux
CAMPTOTHECIN - From Chinese Camptotheca acuminata - P53 mutations that is essential for apoptosis
- Stabilize Topoisomerase I cleavable complex - Decreased expression or mutation of topo-II
- Mechanism of resistance:
- P-glycoprotein drug efflux pump Etoposide:
- Decreased Topoisomerase I expression or affinity to - Oral and IV route
DNA - t1/2: 6-8 hours: renal clearance
- Exposure to Topo I agents leads to expression of - Conditions lowering albumin levels will lead to increased
Topo II free fraction, increasing toxicities

CAMPTOTHECIN: - Representative drug Therapeutic uses:

Irinotecan - Given Intravenously - With Cisplatin: Testicular cancers, SCLCA, NSCLCA
- Converted to active metabolite: SN-38 by - Childhood ALL
carboxylesterase converting enzyme - Non-Hodgkin’s lymphoma
- Major excretion pathway: glucuronidation by UGT1A1
- Patients with Crigler Najjar or Gilbert’s syndrome Toxicity:
are at high risk of severe toxicity - Leukopenia
- REMEMBER: Irinotecan is excreted via - Long term: Acute non-lymphocytic leukemia in children
glucuronidation pathway in the liver. So that if you previously treated for ALL
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 ANTHRACYCLINES - “rubicins” - red drug (Doxorubicin, Epirubicin)
elevated bilirubin levels or those with biliary - Tumor antibiotic from Streptococcus species
obstruction, jaundice patients, and patients with - Still widely used today
bad liver. - Hard to classify because of several MOA’s
- Binds with Topo-II
Clinical Uses: - Generate free radicals
- Metastatic Colorectal cancers: with 5-FU, Leucovorin, or - Intercalates DNA
Capecitabine - Promotes Apoptosis
- SCLCA, NSCLCA, cervical, ovarian, gastric cancer - Mechanisms of resistance
- Decreased activity of Topo-II
Toxicity: - Increased glutathione peroxidase activity (lessens
- Acute diarrhea: cholinergic mediated, associated with free radical generation)
abdominal cramps, salivation, diaphoresis, lacrimation; - Increased P-glycoprotein mediated efflux
prevented by premedication with Atropine (anti-
cholinergic) Common Toxicity:
- Delayed diarrhea: probably SN-38 mediated, addressed - Dose limiting: Cardiotoxicity (CHF)
by loperamide - Doxorubicin: > 450mg/m2 (1-10% incidence)
- Neutropenia - Epirubicin: >900mg/m2
- Presents as Congestive Heart Failure
EPIPODO - From mandrake plant: Podophyllum peltatum - Acute cardiac toxicities: low voltage QRS,
PHYLLOTOXINS - Stabilizes Topo-II cleavable complexes prolonged QT interval, sinus tachycardia
- Resistance mechanisms: - Cardiotoxicity due to Free radicals generated

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 - Heart has increased oxygen tension, rich
mitochondria, and increased iron-containing
myoglobin and hemoglobin
- Epirubicin & Mitoxantrone: less cardiotoxic
- Severe extravasation reactions
- Protect from light for prolonged infusion
- Neutropenia
- Hair loss
- Given intravenously. Bolus or infusional
- Infusional has higher rate of extravasation
- Multiphasic elimination: Liver
Clinical use:
- Doxorubicin: lymphomas, leukemias, breast cancer,
sarcomas, SCLCA
- Daunorubicin: ALL and AML
- Epirubicin: Breast cancer
- Mitoxantrone (Anthracenedione): Acute non-lymphocytic
leukemia, hormone-resistant prostate cancer.
- Liposomal doxorubicin: less cardiotoxic, less neutropenia,
used in ovarian cancer, lymphomas
OTHER TUMOR ANTIBIOTICS
BLEOMYCIN MITOMYCIN
- Causes oxidative damage to DNA - From Streptococcus caespitosus
producing single and double strand - Becomes an alkylating agent after
breaks intracellular enzymatic alterations
- Administered IV, IM, intravesical - Cross links at N6 of adenine and
- Renal exrection: t1/2 3hours O6,N7 of guanine
- IV administration
Clinical uses: - Elimination by chemical conjugation,
- Germ cell tumors and less than 10% excreted in urine
- HL and bile
- NHL
Clinical uses:
Toxicities: - Treatment of anal cancer (given
- Pulmonary fibrosis (cummulative together with radiotherapy)
dose >250U); supportive treatment - Radiosensitizer for anal cancer
- Initial sign is decline in CO2 diffusion - Cervix, stomach, breast, bladder
capacity (intravesical), lung, head and neck
- Little myelosuppression
- Cutaneous toxicity: Toxicity:
hyperpigmentation, keratosis - Myelosuppression
- Most dangerous: HUS
PLATINUM COMPOUNDS
● Forms DNA ‘adducts’ (bulges in DNA structure) which are recognized by
MMR (mismatch repair enzymes) and later leads to cell death.
● Forms intrastrand and interstrand cross-links.
● Enters cells by diffusion
● Resistance:
○ Defects or deficiencies in MMR
○ Increased activity of NER (nucleotide excision repair)
○ Not affected by P-glycoprotein
CISPLATIN - Representative drug
- a.k.a cis-diamminedichloroplatinum (CDDP)
- Given intravenously in normal saline solution
- Initial half life of 25-50 minutes, then terminal of 24
hours
- Photosensitive
- Clinical uses: Germ cell tumors, Lung cancer, head and
neck cancers, ovarian cancer.
- Curative even in advanced germ cell tumors
Toxicity:
- Renal toxicity: tubular damage prevented by hydration
and diuresis
- Myelosuppression
- Ototoxicity (high frequency hearing loss)
- Hypomagnasemia, hypokalemia, hypocalcemia
- Most emetogenic chemotherapeutic drug on planet
Earth
CARBOPLATIN - Less reactive than cisplatin, better tolerated
- Less emetogenic, less nephro/neuro/ototoxicity but
more pronounced neutropenia

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CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
 - Dose computed as: (GFR+25) x AUC Fludarabine
- Excellent oral bioavailability (80-100%)
Clinical uses: - Crosses BBB
- Ovarian cancer, lung cancer, lymphomas, head and neck - Urinary excretion
cancers, bladder cancer, germ cell tumors
- Clinical trials demonstrate equivalence with cisplatin in Clinical uses:
lung and ovarian cancers; inferior in head and neck and - Myeloproliferative diseases: polycythemia, CML,
germ cell tumors thrombocytosis
- Sickle cell disease

OXALIPLATIN - Produces more bulky adducts Toxicity:

- Least affected by MMR abnormalities Long terminal half - Myelosuppression
life (273 hours) - Leukopenia
- Thrombocytopenia
Clinical uses: - Anemia
- GI cancers: Adjuvant and metastatic colorectal cancers;
Gastric cancers REMEMBER: This is the third drug that crosses the BBB
- Ovarian, germ cell, cervical cancer.
MITOTANE - Similar to DDT insecticide
Toxicity: - Preferential attack of adrenal cortical cells
- Dose limiting toxicity: Peripheral Neuropathy - Orally administered
- Less neutropenia
Clinical use:
- Adrenocortical carcinoma/ Adrenal cancer (very rare)

MISCELLANEOUS Toxicity:
- Anorexia, nausea
L-ASPARAGINASE - Enzyme from E. coli - Depletion of endogenous corticosteroids
- Deprives cancer cells of essential L-Asparagine blocking
protein synthesis HORMONAL AGENTS
- Component in regimens for ALL (Acute Lymphoblastic
Leukemia)
ADRENO - Most commonly used:
Toxicity: CORTICOSTEROIDS - Prednisone
- Hypersensitivity reactions (foreign protein) - Dexamethasone
- Minimal BM and GI toxicity - Able to induce remissions in hematologic cancers and
- Hyperglycemia, Hypoalbuminemia, protein C and S responses in solid tumors
deficiency - Lethal to lyphocytes
- Pancreatitis (or severe abdomical pain) - Valuable component in NHL, HL, CLL, ALL
- MOA: Promotes apoptosis (cytotoxic to your WBCs.
HYDROXYUREA - Inhibits enzyme ribonucleoside diphosphate reductase That’s why it’s used in combination with other
(converts ribonucleotides to deoxy) chemotherapy agents such as lymphomas.)
- Favors incorporation of other drugs (Cyta, Gemcitabine,

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 Side effects: cancer treatment (adjuvant or metastatic)
- Immunosuppression
- Glucose intolerance
- Osteoporosis Side effects:
- Water retention - Thrombosis risk
- GI ulcers - Endometrial CA
- Hot flashes, nausea, vomiting
AROMATASE - Most commonly used: - Menstrual irregularities
INHIBITORS - Letrozole
- Anastrozole REMEMBER: Tamoxifen directly binds to estrogen receptors
- Exemestane while aromatase inhibitors will just aim to lower the estrogen
- Inhibits aromatase enzyme that converts androgens to levels in your body.
estrogens
- If you inhibit aromatase, you decrease the ANALOGY:
production of your estrogen. This is beneficial to Aromatase Inhibitors side effects: Bone-related
breast cancer patients who are positive to the Tamoxifen : Blood vessels and endometrial cells-related
estrogen receptor. So you test the tumor if it’s
positive for the estrogen receptor so you can give ANTI-ESTROGENS: - More potent inhibitor of Estrogen Receptors
aromatase inhibitors. FULVESTRANT - Given in cases of failure with tamoxifen treatment.
- Aromatase enzyme in adrenal glands and adipose - Down regulates the ER proteins
tissue. - Has no uterotrophic agonist activity (doesn’t stimulate
- Indicated for post-menopausal ER/PR+ breast cancer endometrial glands)
patients in adjuvant, neoadjuvant, and metastatic - Given intramuscularly every month
setting.
NOTE: Both Tamoxifen and Aromatase inhibitors are given
Side effects: orally as maintenance drugs that the patient takes for 10 years
- Decrease in bone mineral density after breast surgery.
- Bone pain
- Increased fracture rates. GnRH ANALOGS - Prototypes: Goserelin, Leuprolide
- Administered intramuscularly or subcutaneously
ANTI-ESTROGENS: - Binds to Estrogen Receptors preventing binding to - Initially flares/stimulate FSH and LH production by the
TAMOXIFEN DNA pituitary, then later cause negative feedback inhibition
- Eventually decrease autocrine stimulation of breast when given regularly.
cancer cells. - Estrogen levels fall to post-menopausal values
- Has an agonist effect on endometrial cells and (medical menopause/castration)
increases thrombotic risk - Androgen levels fall to castrate values.
- Tamoxifen can have a stimulatory effect to - Used in breast cancer and prostate cancer
endometrial cells. So that’s why when you give
tamoxifen, you also monitor once in a while with ANTI-ANDROGENS - Bicalutamide, Flutamide, Nilutamide
an ultrasound, the thickness of the endometrium. - Binds to Androgen receptors and causes complete
Sometimes it can get so thick that it can develop androgen blockade
into a cancer. - Usually given with GnRH analogs
- Indicated in ER/PR+ pre or post-menopausal breast

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 Side effects:
- Decreased libido MONOCLONAL ANTIBODIES
- Hot flashes
- Gynecomastia MONOCLONAL ANTIBODIES RECEPTOR SIDE EFFECTS
- Mastodynia
- Paradoxical stimulation of androgen receptors (if under TRASTUZUMAB Her2 receptor (breast CA) CHF (esp with
anti-androgens for a very long time) anthracycline)

BIOLOGIC RESPONSE MODIFIERS BEVACIZUMAB VEGF ligand (inhibits Hypertension, bleeding,

angiogenesis) proteinuria

INTERLEUKIN-2 - Not directly cytotoxic CETUXIMAB EGFR receptor (Colorectal Skin rashes
- Expands a T-cell response that is cytolytic for tumor CA; Head & Neck CA)
cells
- Uses: Melanoma, Renal cell carcinoma, AML PANITUMOMAB EGFR receptor (Colorectal
- Toxicity: hypotension, peripheral edema, azotemia CA)

G-CSF - Filgrastim/ Lenograstim: expands population of RITUXIMAB CD20 receptor (B-cell

(GRANULOCYTE- neutrophil precursors (so you don’t get infections) lymphoma)
COLONY - Prophylaxis for chemotherapy induced neutropenia
STIMULATING - Side effects: Fever, chills PERTUZUMAB Inhibits coupling of Her2
FACTOR) proteins
** Common side effect: HYPERSENSITIVITY REACTION
TARGETED (BIOLOGIC) THERAPIES
● Signal transduction TYROSINE KINASE INHIBITORS
○ Relaying outside signals towards the nucleus causing specific gene
expression and transcriptions of proteins promoting cell growth, TYROSINE KINASE INHIBITORS RECEPTOR/TARGET
proliferation, angiogenesis, etc.
● Monoclonal antibodies (Mab’s): Target extracellular receptors or Ligands; IMATINIB (GLEEVEC) Bcr-Abl TKI in CML
Large immunoglobulins CD117 TKI in GIST
● Tyrosine Kinase Inhibitors (TKI’s): Target intracellular receptor; Associated
enzyme (Tyrosine Kinases); Small molecules GEFITINIB EGFR TKI in NSCLCA
● Mab’s and TKI’s:
○ Favorable side effects profile (compared to traditional anti- ERLOTINIB EGFR TKI in NSCLCA and pancreatic cancer
neoplastic drugs)
SUNITINIB Multikinase in renal and liver cancer
○ Cytostatic (drawback; not be able to kill but only prevent
proliferation) SORAFENIB Multikinase in renal and liver cancer
○ Combined with cytotoxic agents
LAPATINIB EGFR and Her2 TKI in breast CA and head and
neck CA

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 AXITINIB AND PAZOPANIB VEGF-R, PDGFR, c-kit in metastatic renal cell
mTOR INHIBITORS
cancer
mTOR (mammalian target of Rapamycin) INHIBITORS
VEMURAFENIB Malignant melanoma bearing mutations in B-Raf
enzyme
mTOR Serine/Threonine kinase involved in signal
CRIZOTINIB c-met and ALK dependent NSCLCA transduction

REGORAFENIB inhibits VEGF-R in metastatic colon cancer EVEROLIMUS For pancreatic neuroendocrine tumors, advances
renal cell cancer, hormone receptor (+) breast
AFATINIB EGFR mutation in NSCLCA cancer
** Common side effects of the first 6 drugs: RASHES, ASTHENIA, WEAKNESS TEMSIROLIMUS Advanced renal cell cancer
** Inhibiting mTOR will PREVENT CELL GROWTH AND PROLIFERATION
PROTEASOME INHIBITORS
● Proteasome: “garbage bin” or “waste basket” of the cell IMMUNE CHECKPOINT INHIBITORS
● aka “Cancer Immunotherapy”
● One of the proposed theories why cancer developed: “cancer is actually a
PROTEASOME INHIBITORS
failure of the immune system where in the cells can no longer recognize an
abnormal cell/s”
BORTEZOMIB Used in multiple myeloma
Adverse events mainly hematologic
IMMUNE CHECKPOINT PROTEINS
● Proteins present on the surface of normal cells that gives an inhibitory
Note: signal to T cells
Proteasome inhibitors blocks ● Protects the normal cells from T cell attack
the action of proteosome,
which breaks down proteins .
● Certain tumor cells “disguise” themselves as “normal” by bearing immune
checkpoint proteins (so they will not be attacked by T cells)
Once IKb is degraded, it will ● PD-1: Programmed Cell Death protein-1
release NFK-b which will cause ○ Found on surface of T cells
cell proliferation, cell survival,
and angiogenesis. Blocking
○ Inhibited by Nivolumab and Pembrolizumab
proteasome will prevents ● PD-2: Programmed Cell Death protein-2
degradation of IKb, thus, no ○ Found on surface of cancer cells, mimicking normal cells
NKb released. ○ Inhibited by Atezolizumab

Figure 5. Proteasome inhibitor

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DR. PAUL DEXTER C. SANTOS
 COMBINATION CHEMOTHERAPY

● Usually a combination of traditional and new biologic agent

● Provides maximal cell kill
● Prevent or slow the subsequent development of drug resistance
● Broader range of interaction between the drugs with different MOA’s and
the heterogenous tumor
● Drugs can be combined if:
○ Each drug is effective as a single agent
Figure 6. The logic behind cancer immunotheraphy. ○ Drugs that cause complete remission are preferred
LEFT: Once the PD-1 of the T cell recognizes the PD-L1 of the tumor cell, it will be ○ If drugs equally effective, choose the ones with less or non-
labeled and this cell will not be “touched” overlapping toxicities
RIGHT: Once PD-1 and PD-L1 is blocked, it will be destroyed by the T cell ○ Drug should not affect each other’s PK
○ Cytotoxics (traditional agents) and biologics (targeted agents)
MOLECULAR PROFILING
● It tells you what genes are present, and what proteins are over-expressed
Note: Why combine drugs with different MOA?
in the cancer cell.
● From these information, appropriate targeting drug is given.
Cancer tumors are believed to be heterogenous. So, combining
drugs with different MOA will target different cells inside the tumor.

ORGAN TEST DRUG TREATMENT

EXAMPLES:
BREAST Her2Neu testing - Trastuzumab ● Mechlorethamine + Dacarbazine: NO
- Lapatinib ○ Both are alkylating agents
- Pertuzumab
○ However, it is sometimes combined
LUNGS EGFR testing - Gefitinib
● Oxaliplatin + Vincristine: NO
- Afatinib ○ Both are neurotoxic
- Erlotinib ● Paclitaxel + Carboplatin: YES
○ Paclitaxel is disposed in the liver while Carboplatin is disposed in
ALK testing - Crizotinib the kidneys.
○ Offers different MOA
● Etoposide + Cisplatin: YES
COLON EGFR T90M mutation - Osimertinib
○ Etoposide is hepatic while Cisplatin is renal
LYMPHOMA Kras testing - Cetuximab ○ Offers different MOA
- Panitumamab ● Paclitaxel + Carboplatin + Bevacizumab: YES
○ Bevacizumab will not have the same side effect profile
GIST/CML cKIT, BcR-Abl testing - Imatinib ● Irinotecan + Cetuximab: YES
- Dasatinib ○ One is cytotoxic drug and the other is a biologic agent
○ Used in treating colon cancers
● Bevacizumab + Erlotinib: YES
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CANCER CHEMOTHERAPY
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 ○ Both biologic agents a. These proteins protect the normal cell from immune attack Incorrect
○ Different side effect profile b. Upon T-cell binding, these proteins give the T-cell the ‘attack’ command
c. These can be present on surface of T-cells or in normal cells
FOR EASIER MEMORIZATION: d. Cancer cells mimicking normal cells have these proteins on their cell membrane

2. This immune checkpoint protein is the target of Nivolumab and Pembrolizumab.

a. EGFR Incorrect
b. MapK
c. K-Ras
d. PD-1

3. A 42 year old male is to be treated with chemotherapy for his Non-Hodgkin’s

Lymphoma. This treatment strategy is called
a. First line therapy
b. Adjuvant therapy Incorrect
c. Neoadjuvant therapy
d. Primary therapy

4. The target enzyme of 5-Flurouracil is:

a. Dihydrofolate reductase Incorrect
b. Tyrosine kinase
c. Thymidylate synthase
d. GARFT

5. The VEGF pathway is responsible for:

a. Neoangiogenesis
b. Contact inhibition
c. Anti-apoptosis
d. Loss of heterozygosity
Note: REMEMBER!!
6. Pulmonary fibrosis is associated with this drug:
a. Doxorubicin
DRUGS THAT CROSSES THE BLOOD- DRUGS THAT ARE GIVEN b. Gemcitabine
BRAIN BARRIER: INTRATHECALLY: c. Fludarabine
▪ High dose methotrexate ▪ Methotrexate d. Bleomycin
▪ Nitrosoureas ▪ Cytarabine
▪ Temozolomide 7. The dose limiting toxicity of Carboplatin is:
▪ Hydroxyurea a. Peripheral neuropathy Incorrect
b. Nephrotoxicity
c. Cardiotoxicity
d. Neutropenia
PAST E 9. Acute onset diarrhea in patients receiving Irinotecan is most likely due to:
a. Cholinergic effect of the drug
1. True of Immune Checkpoint Proteins, EXCEPT:
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CANCER CHEMOTHERAPY
DR. PAUL DEXTER C. SANTOS
 b. Direct toxic effect of SN-38 d. Paclitaxel
c. Generation of MTIC molecules
d. Formation of Acrolein 17. This drug is given for Non-Small Cell Lung Cancer with ALK-MET mutation:
a. Lapatinib
10. Hemorrhagic cystitis is due to this metabolite of Cyclophosphamide and Ifosfamide. b. Trastuzumab
a. SN-38 c. Pertuzumab
b. Acrolein d. Crizotinib
c. Phosphoramide
d. MTIC 18. The following are Topoisomerase interactive agents, EXCEPT:
a. Ixabepilone
11. Cumulative doses of this drug can lead to cardiotoxicity. b. Etoposide
a. Vinorelbine c. Teniposide
b. Methotrexate d. Irinotecan
c. Doxorubicin
d. Docetaxel 19. In which setting is chemotherapy most effective?
a. Indolent, slow growing tumors
12. Nephrotoxicity is the dose limiting side effect of this drug: b. Late stage, bulky disease
a. Carboplatin c. Low tumor burden, high growth rate
b. Cisplatin d. Low growth rate, low tumor burden
c. Bleomycin
d. Mitomycin 20. Which of the following can bind and inhibit the Androgen Receptor?
a. Tamoxifen
13. This drug inhibits the cellular proteasome: b. Fulvestrant
a. Bortezomib c. Exemestane
b. Regorafenib d. Bicalutamide
c. Doxorubicin
d. Erlotinib Answer: B-D-D-C-A-D-D-D-A-B-C-B-A-D-D-D-D-A-C-D

14. The following agents affect the VEGF/Angiogenesis pathway, EXCEPT:

a. Regorafenib
REFERENCES
b. Bevacizumab
c. Pazopanib
d. Cetuximab 1. Batch 2019 Trans
2. PPT presentation
15. This drug inhibits mitosis by destabilizing microtubule: 3. Lecture discussion
a. Docetaxel
b. Paclitaxel TRANSCRIBED BY:
c. Ixabepilone
d. Vincristine 1. Group 10A: Branda, Sayos, Sisracon, Suilen, Sy
2. Subtranshead: Poi, RPh
16. The of the following drugs can cross the blood brain barrier, EXCEPT
a. Temozolomide
b. Carmustine
c. High dose Methotrexate

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