Cancer Chemotherapy

Introduction (cancer chemotherapy):

- Use of cytotoxic anticancer drugs:
▪ Caused high rates of cure of a few cancers, as:
➔ Acute lymphocytic leukemia in children & Testicular cancer & Hodgkin’s lymphoma
▪ Without chemotherapy → extremely high mortality rates
▪ Some types of cancer are barely affected by currently available drugs.
- Cytotoxic anticancer drugs are more toxic than any other drugs →benefit must be carefully weighed
against risks.
▪ Usually act on all dividing cells (cancerous or normal).
- Ultimate goal:
▪ The use of advances in cell biology to develop targeted therapies that selectively affect specific
cancer cells.

Anti-cancer drugs:
- Alkylating▪agents: - Antitumor antibiotics
▪ Cyclophosphamide ▪ Bleomycin
▪ Cisplatin ▪ Doxorubicin
- Antimetabolites: ▪ Mitomycin
▪ 5-fluorouracil - Proteasome inhibitors:
▪ Methotrexate ▪ Bortezomib
▪ Gemcitabine ▪ Carfilzomib
▪ 6-mercaptopurine - Hormonal:
- Natural products: ▪ Prednisone
▪ Etopside ▪ Tamoxifen
▪ Paclitaxel - Miscellaneous
▪ Vincristine ▪ Imatinib
▪ Cetuximab
Cancer cell cycle kinetics
- G1 phase → S phase → G2 phase → M phase
- G 0 phase means the cell is not divided.
- The best target to kill the cell is at the (G1, S- phase).
- Some anticancer drugs are selective on cycling cells (cell cycle-specific
drugs)
▪ Usually most effective when cells are in a specific phase of the cell
cycle
- Other drugs are cell cycle-nonspecific drugs.
▪ Kill tumor cells in both cycling and resting phases of cell cycle
➔ Cycling cells are more sensitive.
- Both types of drugs are most effective when most tumor cells are
proliferating (when growth fraction is high).

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❖ The Log-Kill Hypothesis
- First-order kinetics:
▪ Most anticancer drugs act with first order kinetics
- Murine model of leukemia:
▪ In this model → All cells are actively progressing through cell cycle
▪ A given dose → kills a constant proportion of cell population rather
than a constant number.
- Log-kill hypothesis:
▪ Proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic function.
▪ Ex: 3-log-kill dose of effective drug → reduces cancer cell population of 1012 cells to 109 (total kill
of 999 × 109 cells)
➔ The same dose reduces the starting population of 106 cells to 103 cells (kill of 999 × 103).
▪ In both cases → the dose reduces numbers of cells by 3 orders of magnitude, or “3 logs.”
- Regarding hematological malignancies:
▪ An inverse relationship between tumor cell number and curability
▪ The growth is exponential.
- Most human solid tumors don’t grow in an exponential manner → rather, the growth fraction of tumor
decreases with time due to blood supply limitations and other factors.
▪ In drug-sensitive solid tumors → response to chemotherapy depends on where the tumor is in its
growth curve.
Resistance to Anticancer Drugs
- Major problem in cancer chemotherapy
- Mechanisms:
1. Increased DNA repair
➔ Increased rate of DNA repair in tumor cells ca
➔ Important for resistance to alkylating agents and cisplatin
2. Formation of trapping agents
➔ Ex: thiol trapping agents (glutathione)
➔ These agents interact with anticancer drugs → form reactive electrophilic species.
➔ Occurs to alkylating agent: bleomycin, cisplatin, and anthracyclines.
3. Changes in target enzymes:
➔ Changes in drug sensitivity of target enzyme or Increased synthesis of enzymes
➔ Ex: Dihydrofolate reductase become less sensitive to the drug (methotrexate)
4. Decreased activation of prodrugs:
➔ Ex: purine antimetabolites (mercaptopurine, thioguanine) and pyrimidine antimetabolites
(cytarabine, fluorouracil) are less activated to their cytotoxic metabolites by tumor cell
enzymes.
5. Inactivation of anticancer drugs:
➔ Increased enzymes that inactivate anticancer drugs
➔ Ex: resistance to purine and pyrimidine antimetabolites.
6. Decreased drug accumulation:
➔ Multidrug resistance due to increased expression of normal gene (MDR1) for a cell surface
glycoprotein (P-glycoprotein) → involved in accelerated efflux of many anticancer drugs.

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Strategies of anticancer chemotherapy
- Cancer Treatment Modalities:
▪ Primary induction chemotherapy:
▪ Primary treatment for:
➔ Many hematologic cancers
➔ advanced solid tumors when no alternative treatment exists.
▪ can be curative in small number of patients who present with advanced metastatic disease
(lymphoma, acute myelogenous leukemia, germ cell cancer, choriocarcinoma, and several childhood
cancers)
➔ in many cases → the goal of therapy are palliation of symptoms, improved quality of life,
increased time to tumor progression.
▪ Neoadjuvant chemotherapy:
➔ Use of chemotherapy for localized cancer when alternative local therapy (surgery) exists.
➔ Goal; to reduce the size of the tumor → surgical resection becomes more feasible (more
effective).
▪ Adjuvant chemotherapy:
➔ Used for many solid tumors
➔ important adjuvant to local treatment procedures (surgery or radiation).
➔ Goal:
 Reduce the risk of local and systemic recurrence
 Improve disease-free & overall survival.
Principles of Combination Therapy
- Combinations of anticancer drugs:
▪ Increases log-kill markedly
▪ Sometimes → synergistic effects are achieved.
▪ Cytotoxic to a heterogeneous population of cancer cells
▪ Prevent development of resistant clones.
▪ Combinations of CCS & CCNS:
➔ Cytotoxic to both dividing and resting cancer cells.
- Principles:
▪ Each drug should be active when used alone against the particular cancer.
▪ Drugs should have different mechanisms of action.
▪ Cross-resistance between drugs should be minimal.
▪ Drugs should have different toxic effects.

- Rescue Therapy
▪ Toxic effects of anticancer drugs can sometimes be alleviated by rescue strategy.
▪ Ex: high doses of methotrexate is given for 36-48h → terminated before severe toxicity occurs to
GI & bone marrow cells.
➔ Leucovorin (tetrahydrofolate) → accumulated more readily by normal cells compared with
neoplastic cells → rescue of normal cells because leucovorin bypasses the dihydrofolate
reductase step in folic acid synthesis (methotrexate prevents synthesis of folate → normal cell
can use leucovorin as a source of folate→ no toxicity→ rescue).
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 ➔ Mercapto-ethane-sulfonate (mesna)→ traps acrolein released from cyclophosphamide →
reduces incidence of hemorrhagic cystitis.

➔ Dexrazoxane→ inhibits free radical formation & affords protection against cardiac toxicity of
anthracyclines (doxorubicin).

The Drugs
Alkylating Agents
- Examples:
▪ Nitrogen mustards (chlorambucil, cyclophosphamide, mechlorethamine)
▪ Nitrosoureas (carmustine, lomustine)
▪ Alkyl sulfonates (busulfan).
▪ Tetrahydroisoquinolines: lurbinectedin and trabectedin.
- Some drugs act in part as alkylating agents: cisplatin, dacarbazine, procarbazine.
- Mechanism of action:
▪ Alkylating agents are CCNS drugs.
➔ Form reactive molecular species → alkylate nucleophilic groups on DNA bases (N-7 position
of guanine) →leads to cross-linking of bases → abnormal base-pairing → DNA strand
breakage.
▪ Tumor cell resistance:
➔ Increased DNA repair
➔ Decreased drug permeability
➔ Increased expression or activity of glutathione.
 Conjugate alkylating agents.

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1. Cyclophosphamide
▪ Pharmacokinetics:
➔ Hepatic cytochrome P450 mediated biotransformation of cyclophosphamide is needed for
antitumor activity.
➔ Converted to 4-hydroxycyclophosphamide in equilibrium with aldophosphamide → both
delivered to tumor and normal tissues
➔ Nonenzymatic cleavage of aldophosphamide: Phosphoramide mustard and Acrolein

▪ Clinical use:
➔ Leukemia, non-Hodgkin’s lymphoma, breast and ovarian cancers, neuroblastoma.
▪ Toxicity:
➔ Expected adverse effects: GI distress, myelosuppression, alopecia
➔ Delayed toxicity: Hemorrhagic cystitis:
 Due to formation of acrolein & Decreased by: 1) vigorous hydration.
➔ Cardiac dysfunction
➔ Pulmonary toxicity
➔ SIADH.

2. Mechlorethamine
▪ Mechanism of action:
➔ Spontaneously converted in the body to a reactive cytotoxic product.
▪ Clinical use:
➔ In regimens for Hodgkin’s & non-Hodgkin’s lymphoma.
▪ Toxicity:
➔ Common: GI distress, myelosuppression (anemia, leukopenia, thrombocytopenia), alopecia.
➔ Marked vesicant (blister-forming) actions.
➔ Delayed toxicity→ Moderate depression of peripheral blood count; excessive doses produce
severe bone marrow depression with leukopenia, thrombocytopenia, and bleeding.

3. Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)

▪ Pharmacokinetics:
➔ IV use
➔ Distribute to most tissues
➔ Cleared by the kidney in unchanged form.
▪ Clinical use:
➔ Commonly used as a component of regimens for testicular carcinoma and bladder, lung, and
ovary cancers
➔ Oxaliplatin is used in advanced colon cancer.
▪ Toxicity:
➔ Cisplatin:
 GI distress
 Mild hematotoxicity
 Neurotoxicity (peripheral neuritis & acoustic nerve damage)
 Nephrotoxicity: reduced by mannitol use with forced hydration.
 Delayed toxicity→ Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve
dysfunction.
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 ➔ Carboplatin:
 Less nephrotoxic than cisplatin
 Less likely to cause tinnitus and hearing loss,
 Greater myelosuppressant actions.
 Delayed toxicity→ Nephrotoxicity, peripheral sensory neuropathy, ototoxicity, nerve
dysfunction.

➔ Oxaliplatin:
 Dose-limiting is neurotoxicity.
 Delayed toxicity→ Myelosuppression, peripheral sensory neuropathy, GI toxicity with
diarrhea and/or mucositis.
 Second line therapy in combination with 5fluorouracil (5FU) and leucovorin, termed the
FOLFOX regimen, for metastatic CRC.

4. Procarbazine
▪ Mechanisms:
➔ Reactive agent → forms hydrogen peroxide → generates free radicals → DNA strand scission.
▪ Pharmacokinetics:
➔ Orally active
➔ Penetrates into most tissues even the cerebrospinal fluid.
▪ Elimination: hepatic metabolism.
▪ Clinical use:
➔ Primary use: as regimens for Hodgkin’s, non-Hodgkin’s lymphoma & brain tumors.
▪ Toxicity:
➔ Myelosuppression
➔ Leukemogenic drug → can cause leukemia.
➔ GI irritation & Skin reactions
➔ CNS dysfunction, Peripheral neuropathy
➔ Disulfiram-like reactions with ethanol
➔ Procarbazine inhibits monoamine oxidase and hepatic drug metabolizing enzymes.
➔ Delayed toxicity → Myelosuppression, hypersensitivity reactions

5. Other Alkylating Agents

▪ Busulfan:
➔ Used for chronic myelogenous leukemia (CML)
➔ Toxicity: Adrenal insufficiency, pulmonary fibrosis, skin pigmentation.
▪ Carmustine & lomustine (Nitrosoureas):
➔ Highly lipid-soluble thus Used as adjuncts for brain tumors.
➔ Non-cross resistant with other alkylating agents.
➔ Alkylation action occurs on N7 position of guanine in DNA
➔ The critical alkylation responsible for cytotoxicity appears to be on O6 position of guanine→
G-C cross links in DNA → responsible for cytotoxicity.
➔ Delayed toxicity→ Myelosuppression; rarely interstitial lung disease (ILD) and interstitial
nephritis.

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 ▪ Dacarbazine:
➔ Used for Hodgkin’s lymphoma.
➔ Toxicity: alopecia, skin rash, GI distress, myelosuppression (Dose limiting toxicity:),
phototoxicity & flu-like syndrome.
➔ Potent vesicant → caution to avoid extravasation during administration.
➔ Delayed toxicity→ Myelosuppression, central nervous system toxicity with neuropathy, ataxia,
lethargy, and confusion.

▪ Lurbinectedin: Delayed toxicity→ Myelosuppression,hepatotoxicity

▪ Trabectedin: Delayed toxicity→ Cardiac toxicity, pulmonary toxicity, skin rash & dermatitis
Antimetabolites
- Structurally Similar to endogenous compounds
- They are antagonists of:
▪ Folic acid (methotrexate)
▪ Purines (mercaptopurine, thioguanine)
▪ Pyrimidines (fluorouracil, cytarabine, gemcitabine).
▪ CCS drugs → acting primarily on S phase of cell cycle.
- Effects: cytotoxic effects on neoplastic cells and have immunosuppressant actions.
1. Methotrexate
▪ Mechanisms of action:
➔ Inhibits dihydrofolate reductase → decrease synthesis of thymidylate, purine nucleotides, and
amino acids → interferes with nucleic acid & protein metabolism
➔ Acts by formation of polyglutamate derivatives of methotrexate
▪ Resistance:
➔ decreased drug accumulation
➔ changes in drug sensitivity or activity of dihydrofolate reductase
➔ decreased formation of polyglutamates.
▪ Pharmacokinetics:
➔ Oral & IV methotrexate has good tissue distribution except to the CNS.
➔ Methotrexate is not metabolized
➔ clearance is dependent on renal function.
➔ Adequate hydration is needed to prevent crystallization in renal tubules.
▪ Clinical use:
➔ choriocarcinoma, acute leukemias, non-Hodgkin’s, primary CNS lymphomas, and many solid
tumors (breast cancer, head and neck cancer, and bladder cancer).
➔ At lower doses in rheumatoid arthritis, psoriasis, and ectopic pregnancy
▪ Toxicity:
➔ Common adverse effects:
BM suppression, toxic effects on skin and GI mucosa (mucositis).
➔ Toxic effects are reduced by administration of folinic acid (leucovorin) (leucovorin rescue).
➔ Long-term use of methotrexate causes hepatotoxicity, pulmonary infiltrates and fibrosis.

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2. Mercaptopurine (6-MP) & Thioguanine (6-TG):
▪ Mechanisms of action:
➔ Purine antimetabolites.
➔ Both drugs are activated to toxic nucleotides by hypoxanthine-guanine phosphoribosyl-
transferases (HGPRTases) → then, they inhibit enzymes involved in purine metabolism.
▪ Resistance:
➔ Decreased activity of HGPRTase
➔ increase production of alkaline phosphatases that inactivate the toxic nucleotides.
▪ Pharmacokinetics:
➔ low oral bioavailability because of first-pass metabolism.
➔ 6-MP is metabolized by xanthine oxidase
 Xanthine oxidase is inhibited by xanthine oxidase inhibitors (allopurinol & febuxostat).

▪ Clinical use:
➔ Mainly for acute leukemias & chronic myelocytic leukemia.
▪ Toxicity:
➔ Dose limiting: Bone marrow suppression
➔ Hepatic dysfunction (cholestasis, jaundice, necrosis).

3. Fluorouracil (5-FU):
▪ Mechanism of action:
➔ Fluorouracil is converted to 5-fluoro2′-deoxyuridine-5′-monophosphate (5-FdUMP) → inhibits
thymidylate synthase → leads to “thymineless death” of cells.
➔ FdUMP is also incorporated into DNA → inhibits DNA synthesis
➔ Also converted to 5-fluorouridine5′-triphosphate (FUTP)→ incorporated into RNA →
interferes with RNA processing and function.
▪ Resistance:
➔ Decreased activation of 5-FU
➔ Increased thymidylate synthase activity
➔ Reduced drug sensitivity of the enzyme.
▪ Pharmacokinetics:
➔ Given IV
➔ Widely distributed, including cerebrospinal fluid.
▪ Elimination: Mainly by metabolism.
▪ Clinical use:
➔ Bladder, breast, colon, anal, head and neck, liver, and ovarian cancers.
➔ Can be used topically for keratoses and superficial basal cell carcinoma
▪ Toxicity: Common: GI distress, myelosuppression, and alopecia.

4. Cytarabine (ARA-C)
▪ Mechanisms of action:
➔ Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite.
➔ activated by kinases to AraCTP (inhibitor of DNA polymerase).
➔ The most specific for S phase of cell cycle among all antimetabolites.

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 ▪ Resistance:
➔ Decreased uptake
➔ Decreased conversion to AraCTP.
5. Gemcitabine:
▪ Mechanism of action:
➔ Deoxycytidine analog
➔ Converted into the active diphosphate and triphosphate nucleotide form.
➔ Gemcitabine diphosphate inhibits ribonucleotide reductase → diminish the pool of
deoxyribonucleoside triphosphates required for DNA synthesis.
➔ Gemcitabine triphosphate is incorporated into DNA → causes chain termination.
▪ Pharmacokinetics: Eliminated mainly by metabolism.
▪ Clinical use:
➔ Initially approved for pancreatic cancer
➔ Now, widely used for non-small cell lung cancer, bladder cancer, and non-Hodgkin’s lymphoma.
▪ Toxicity:
➔ Myelosuppression (mainly neutropenia)- dose limiting.
➔ Pulmonary toxicity.
6. TAS-102:
▪ Inactive in its parent form.
▪ Oral fluoropyrimidine analog
▪ Retains clinical activity in 5FUresistant tumor
▪ Made up of two main components combined in a 1:0.5 molar ratio:
➔ Trifluridine (a fluorinated pyrimidine nucleoside)→ triphosphate form into DNA.
 inhibits TS, albeit a much weaker TS inhibitor than the 5FU metabolite FdUMP, and also
to the triphosphate form, which is directly incorporated into DNA, leading to inhibition of
DNA synthesis and function.
➔ Tipiracil (a thymidine phosphorylase (TP) inhibitor)
 inhibit TP, a key enzyme that degrades trifluridine to inactive forms
 allows for higher levels of trifluridine, which can then be metabolized to the active
nucleotide metabolite forms
▪ Used for: treatment of refractory, metastatic CRC
▪ Dose limiting toxicity: myelosuppression appears as (neutropenia more commonly
observed than anemia and thrombocytopenia).
▪ Side effects: GI toxicity with diarrhea and nausea/vomiting, fatigue, and anorexia
Natural products anticancer drugs
- Plant-derived CCS drugs
- Ex: vinca alkaloids (vinblastine, vincristine, vinorelbine), podophyllotoxins (etoposide, teniposide),
camptothecins (topotecan, irinotecan), taxanes (paclitaxel, docetaxel)
1. Vinblastine, Vincristine, and Vinorelbine
▪ Mechanism of action of vinca alkaloids:
➔ Block formation of mitotic spindle by preventing the assembly of tubulin dimers into
microtubules.
➔ Act primarily in M phase of cancer cell cycle.
▪ Resistance: increased efflux of drugs from tumor cells via membrane drug transporter.

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 ▪ Pharmacokinetics:
➔ Must be given parenterally.
➔ Penetrate most tissues except cerebrospinal fluid.
➔ Cleared mainly via biliary excretion.
▪ Clinical use
➔ Vincristine: acute leukemias, lymphomas, Wilms’ tumor, neuroblastoma.
➔ Vinblastine: lymphomas, neuroblastoma, testicular carcinoma, Kaposi’s sarcoma.
➔ Vinorelbine: non-small cell lung cancer & breast cancer
▪ Toxicity
➔ Vinblastine and vinorelbine: GI distress, alopecia, bone marrow suppression.
➔ Vincristine doesn’t cause serious myelosuppression
 Causes neurotoxicity
 Areflexia, peripheral neuritis, and paralytic ileus
2. Etoposide and Teniposide
▪ Mechanism of action:
➔ Semisynthetic derivative of podophyllotoxin → DNA breakage through inhibition of
topoisomerase II.
 Most active in late S and early G2 phases of cell cycle.
▪ Pharmacokinetics:
➔ Well absorbed after oral administration
➔ Distributes to most body tissues.
▪ Elimination: mainly by the kidneys → dose reductions in renal impairment.
▪ Clinical use: used in combination regimens for lymphoma, lung, germ cell, and gastric cancers.
▪ Toxicity: GI irritations, alopecia & bone marrow suppression.

3. Topotecan and Irinotecan

▪ Mechanism of action:
➔ 2 camptothecins (topotecan and irinotecan) → produce DNA damage by inhibiting
topoisomerase I.
 Damage DNA by inhibiting the enzyme that cuts and religates single DNA strands during
normal DNA repair processes.
▪ Pharmacokinetics:
➔ Irinotecan: prodrug converted in the liver into an active metabolite (SN-38).
 Eliminated in the bile and feces
 Genetic variation affects irinotecan metabolism
 Toxicity: In patients with variants of UGT1A → low glucuronidation activity →
accumulation of the drug
➔ Topotecan: eliminated renally.

▪ Clinical use:
➔ Topotecan: second-line therapy for advanced ovarian cancer and for small cell lung cancer.
➔ Irinotecan: used for metastatic colorectal cancer.
▪ Toxicity:
➔ Myelosuppression & diarrhea are the 2 most common toxicities.

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4. Paclitaxel and Docetaxel
▪ Mechanism of action:
➔ Paclitaxel & docetaxel interfere with mitotic spindle.
➔ Act differently from vinca alkaloids
➔ They prevent microtubule disassembly into tubulin monomers
▪ Pharmacokinetics:
➔ Given IV.
▪ Clinical use:
➔ Many solid tumors (breast, ovarian, lung, gastroesophageal, prostate, bladder, and head and
neck cancers)
▪ Toxicity:
➔ Neutropenia, thrombocytopenia, high incidence of peripheral neuropathy, hypersensitivity
reactions during infusion.
➔ Neurotoxicity & bone marrow depression.

5. Liposomal irinotecan:
▪ In combination with 5FU and leucovorin for the treatment of metastatic adenocarcinoma of the
pancreas after disease progression following gemcitabine based therapy
▪ Toxicities: myelosuppression and GI toxicity with diarrhea and nausea/vomiting

6. Deruxtecan:
▪ 10-fold more potent inhibitor of topo I than SN38
▪ It is conjugated with trastuzumab to form an antibody drug conjugate (ADC).
▪ The activity of this molecule is dependent on HER expression and not on HER2 gene amplification,
which is in contrast to other antiHER2 inhibitors.
Antitumor antibiotics
- Ex: anthracyclines, bleomycin, and mitomycin
1. Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone)
▪ CCNS drugs
▪ MOA:
➔ Intercalate between DNA base pairs → inhibit topoisomerase II & generate free radicals.
➔ Block the synthesis of RNA and DNA → DNA strand scission.
➔ Causes also membrane disruption
▪ Pharmacokinetics:
➔ Doxorubicin & daunorubicin are given IV.
➔ Metabolized in the liver → the products are excreted in bile and urine.
▪ Clinical use:
➔ Doxorubicin: Hodgkin’s & nonHodgkin’s lymphoma, myelomas, sarcomas, breast, lung, ovarian,
and thyroid cancers.
➔ Daunorubicin: mainly for treatment of acute leukemias.
➔ Idarubicin (newer anthracycline): acute myelogenous leukemia.
➔ Epirubicin: breast & gastroesophageal cancer.
➔ Mitoxantrone: acute myeloid leukemias, non-Hodgkin’s lymphoma, breast cancer, and
gastroesophageal cancer.

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 ▪ Toxicity:
➔ Bone marrow suppression, GI distress, & severe alopecia.
➔ Most distinctive adverse effect: cardiotoxicity
 Initial electrocardiographic abnormalities (arrhythmias)
 Slowly developing, dose-dependent cardiomyopathy
 Heart failure.
➔ Dexrazoxane (inhibitor of iron-mediated free radical generation)→ protect against dose-
dependent form of cardiotoxicity.
➔ Liposomal formulations of doxorubicin is less cardiotoxic

2. Bleomycin
▪ Mechanism of action:
➔ Mixture of glycopeptides that generates free radicals → bind to DNA →strand breaks & inhibit
DNA synthesis.
➔ CCS drug active in G2 phase of tumor cell cycle
▪ Pharmacokinetics:
➔ Given parenterally.
➔ Inactivated by tissue aminopeptidases and by renal clearance in an intact form
▪ Clinical use:
➔ Component of drug regimens for Hodgkin’s lymphoma & testicular cancer.
➔ Lymphomas & squamous cell carcinomas.
▪ Toxicity:
➔ Pulmonary dysfunction (pneumonitis, fibrosis)
 Develops slowly & it is the dose limiting.
➔ Hypersensitivity reactions (chills, fever, anaphylaxis) → common
➔ Mucocutaneous reactions (alopecia, blister formation, hyperkeratosis).
3. Mitomycin
▪ Mechanism:
➔ CCNS drug
➔ Metabolized by liver enzymes to form alkylating agent that cross-links DNA.
▪ Pharmacokinetics:
➔ Given intravenously
➔ Rapidly cleared via hepatic metabolism.
▪ Clinical use:
➔ Acts against hypoxic tumor cells
➔ Used in combination regimens for adenocarcinomas of the cervix, stomach, pancreas, and lung.
▪ Toxicity:
➔ Severe myelosuppression
➔ Toxic to the heart, liver, lung, and kidneys.

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Miscellaneous Anticancer Agents
1. Tyrosine Kinase Inhibitors (Imatinib)
▪ Selective anticancer drug
▪ MOA:
➔ Bcr-abl oncogene (Philadelphia chromosome translocation) produces a protein oncogene →
imatinib inhibits tyrosine kinase activity that results from this protein
➔ This gene is commonly expressed in chronic myelogenous leukemia (CML)
▪ Use:
➔ CML
➔ GI stromal tumors that express c-kit tyrosine kinase.
▪ Resistance: mutation of bcr-abl gene.
▪ Toxicity: diarrhea, myalgia, fluid retention, congestive heart failure.
▪ Another examples: Dasatinib, nilotinib, and bosutinib, Ponatinib, Asciminib.

▪ Ponatinib:
➔ Potent inhibitor of the BcrAbl tyrosine kinase
➔ Inhibits all known mutant forms of BCRABL, including the gatekeeper mutation T315I.
➔ Has broader spectrum and inhibits a wide range of tyrosine kinases, including:
 Members of VEGFR, PDGF, FGF, Flt3, TIE2, Src family kinases, Kit, TET, and EPH.
➔ Used for:
 CML that is resistant or intolerant to prior TKI therapy
 for Ph+ ALL that is resistant or intolerant to prior TKI therapy.

▪ Asciminib:
➔ Small molecule allosteric inhibitor
➔ targets the myristoyl pocket of BcrAbl
➔ induces and stabilizes an inactive conformation of the kinase.
➔ Used for: Ph+ CP CML
➔ Metabolized mainly in the liver by: CYP3A4
➔ No dose adjustment is required with mild to severe hepatic and/or renal impairmen.
➔ Side effects: myelosuppression, pancreatitis, hypertension, mild nausea and vomiting, fatigue,
and musculoskeletal pain

2. Growth Factor Receptor Inhibitors

▪ Trastuzumab (monoclonal antibody):
➔ Recognizes HER-2/neu receptor for epidermal growth factor (surface protein in breast cancer)
➔ Acute toxicity: nausea, vomiting, chills, fevers, and headache.
➔ Toxicity: cardiac dysfunction (heart failure)

- The EGFR regulates signaling pathways involved in cellular proliferation, invasion and metastasis, and
angiogenesis.
- Also implicated in inhibiting the cytotoxic activity of some anticancer drugs and radiation therapy.
▪ Cetuximab:
➔ Chimeric monoclonal antibody directed to the extracellular domain of the EGFR.
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 ➔ Combined with irinotecan and oxaliplatin for metastatic colon cancer
➔ Combined with radiation for head and neck cancer.
➔ Primary toxicity: skin rash & hypersensitivity infusion reaction.
➔ Black box warning: low but real increased risk (1%) of sudden death.

▪ Panitumumab:
➔ Fully human monoclonal antibody directed against EGFR.
➔ Approved for refractory metastatic colorectal cancer.

▪ Gefitinib & erlotinib:

➔ Small molecule inhibitors of EGFR’s tyrosine kinase domain.
➔ Used as second-line agents for non-small cell lung cancer
➔ Erlotinib is also used in combination therapy of advanced pancreatic cancer.
➔ Main toxicity: Rash and diarrhea.

▪ Bevacizumab:
➔ Monoclonal antibody → binds to vascular endothelial growth factor (VEGF) → prevents it
from interacting with VEGF receptors.
➔ VEGF is important for angiogenesis required for tumor metastasis.
➔ Used in: colorectal, breast, non-small cell lung, and renal cancer.
➔ Adverse effects: hypertension, infusion reactions, arterial thrombosis, impaired wound healing,
gastrointestinal perforation, and proteinuria.

▪ Ziv-aflibercept:
➔ Interferes with VEGF function.
➔ Recombinant fusion protein of VEGF binding portions from the extracellular domains of human
VEGF receptors 1 and 2, fused to the Fc portion of human IgG1.
▪ Sorafenib, sunitinib, and pazopanib:
➔ Small molecules that inhibit multiple receptor tyrosine kinases (RTKs)
➔ Metabolized by CYP3A4
➔ Elimination is primarily hepatic.
➔ Most common adverse effects: Hypertension, bleeding complications, and fatigue.
▪ Rituximab
➔ A monoclonal antibody that binds to a surface protein in non-Hodgkin’s lymphoma cells
➔ MOA:
 Complement-mediated lysis
 Direct cytotoxicity
 Induction of apoptosis.
➔ Combined with conventional anticancer drugs (cyclophosphamide + vincristine + prednisone)
in low-grade lymphomas.
➔ Adverse effects: hypersensitivity reactions & myelosuppression.

14 Moath E Bani Salem

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Mohammad Alomari
▪ Interferons
➔ Endogenous glycoproteins
➔ Have antineoplastic, immunosuppressive, and antiviral actions.
➔ Alpha-interferons are effective against:
 Hairy cell leukemia, Early stage of CML & T-cell lymphomas.
➔ Toxic effects: myelosuppression & neurologic dysfunction
▪ Asparaginase
➔ Enzyme that depletes serum asparagine
➔ Given intravenously.
➔ Used in:
 T-cell auxotrophic cancers (leukemia and lymphomas) that require exogenous asparagine
for growth.
➔ Adverse effects: severe hypersensitivity reactions, acute pancreatitis, and bleeding.

▪ Proteasome Inhibitors (Bortezomib & carfilzomib):

➔ Inhibitors of chymotrypsin like activity of 26S proteasome in mammalian cells.
➔ The 26S proteasome:
 Large protein complex that degrades ubiquitinated proteins (cyclin-dependent kinases)
 Inhibition of this protein → down-regulation of nuclear factor kappa B (NF-κB) signaling
pathway.
➔ Used for: treatment of multiple myeloma
➔ Adverse effects:
 Peripheral neuropathy, thrombocytopenia, heart failure, and hypotension.

▪ Necitumumab:
➔ Fully human IgG1 monoclonal antibody
➔ MOA: inhibition of the EGFR signaling pathway

▪ Afatinib:
➔ Small molecule inhibitor of the tyrosine kinase domains of EGFR, HER2, and HER4.
➔ Causes inhibition of downstream ErbB signaling
➔ first line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R
mutations.

▪ Osimertinib:
➔ Side effects like (erlotinib and afatinib),
➔ Unique cardiac toxicities as QTc prolongation and cardiomyopathy.

▪ Ramucirumab:
➔ IgG1 antibody that directly targets the VEGFR2 receptor.
➔ This antibody inhibits binding of the VEGF ligands VEGFA, VEGFC, and VEGFD to the VEGFR2
receptor.

15 Moath E Bani Salem

0779209047
Mohammad Alomari
 17 Moath E Bani Salem
0779209047
Mohammad Alomari
 18 Moath E Bani Salem
0779209047
Mohammad Alomari