Cancer

Chemotherapy
DR.AMMARA BUTT
CANCER CELL CYCLE KINETICS
A. CELL CYCLE KINETICS
Cancer cell population kinetics and the cancer cell cycle significantly
influence the actions and clinical applications of anticancer drugs.
Some drugs act selectively on cycling cells, known as cell cycle-specific
(CCS) drugs, while others affect tumor cells in both cycling and resting
phases of the cell cycle, termed cell cycle-nonspecific (CCNS) drugs.
CCS drugs are typically most effective when cells are in a specific phase of
the cell cycle, maximizing their impact during that particular stage.
Both CCS and CCNS drugs exhibit optimal efficacy when a large proportion
of tumor cells are actively proliferating (indicating a high growth fraction
within the tumor.)
CANCER CELL CYCLE KINETICS
B. THE LOG-KILL HYPOTHESIS

Cytotoxic drugs in leukemia models follow first-order kinetics.

The log-kill hypothesis indicates that drug effectiveness is logarithmic.
There's an inverse relationship between tumor size and curability.
Human solid tumors don't grow exponentially, and growth fraction decreases over
time.
Chemotherapy response in drug-sensitive tumors depends on tumor growth stage.
CANCER CELL CYCLE KINETICS
C. RESISTANCE TO ANTICANCER DRUGS
Drug resistance is a major problem in cancer chemotherapy. Mechanisms of
resistance include the following:
1. Increased DNA repair—An increased rate of DNA repair in tumor cells can be
responsible for resistance and is particularly important for alkylating agents and
cisplatin.
2. Formation of trapping agents—Some tumor cells increase their production of
thiol trapping agents (eg, glutathione), which interact with anticancer drugs that form
reactive electrophilic species. This mechanism of resistance is seen with the alkylating
agent bleomycin, cisplatin, and the anthracyclines.
CANCER CELL CYCLE KINETICS
C. RESISTANCE TO ANTICANCER DRUGS
3. Changes in target enzymes—Changes in the drug sensitivity of a target enzyme,
dihydrofolate reductase, and increased synthesis of the enzyme are mechanisms of
resistance of tumor cells to methotrexate.
4. Decreased activation of prodrugs—Resistance to the purine antimetabolites
(mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine,
fluorouracil) can result from a decrease in the activity of the tumor cell enzymes needed
to convert these prodrugs to their cytotoxic metabolites.
5. Inactivation of anticancer drugs—Increased activity of enzymes capable of
inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the
purine and pyrimidine antimetabolites.
6. Decreased drug accumulation—
This form of multidrug resistance involves increased expression of the MDR1 gene, which
encodes P-glycoprotein. P-glycoprotein functions as a transport molecule, accelerating
the efflux of many anticancer drugs in resistant cells.
STRATEGIES IN CANCER CHEMOTHERAPY
A. CANCER TREATMENT MODALITIES
Chemotherapy is used in three main clinical settings:
1. Primary induction chemotherapy
Drug therapy serves as the primary treatment for many hematologic cancers
and advanced solid tumors, particularly when alternative treatment options
are limited.
While primary induction therapy can achieve cure in a minority of patients
with advanced metastatic disease, the objectives of therapy often focus on
palliating cancer symptoms, enhancing quality of life, and prolonging time to
tumor progression.
STRATEGIES IN CANCER CHEMOTHERAPY
A. CANCER TREATMENT MODALITIES
2. Neoadjuvant chemotherapy
The use of chemotherapy in patients who present with localized cancer for which
alternative local therapy, such as surgery, exist is known as neoadjuvant chemotherapy.
The goal is to render the local therapy more effective.
3. Adjuvant chemotherapy—In the treatment of many solid tumors, chemotherapy
serves as an important adjuvant to local treatment procedures such as surgery or
radiation. The goal is to reduce the risk of local and systemic recurrence and to improve
disease-free and overall survival.
STRATEGIES IN CANCER CHEMOTHERAPY
B. PRINCIPLES OF COMBINATION THERAPY OF THE PROJECT
Combining different anticancer drugs in chemotherapy can significantly increase cell
kill, often working better together than alone. This approach targets various types of
cancer cells and can prevent the development of drug resistance. Using a mix of drugs
that act at different points in the cell cycle can kill both dividing and resting cancer cells.
Important principles for choosing drug combinations include selecting drugs with
complementary mechanisms of action and considering their toxicity profiles.
(1) Each drug should be active when used alone against the particular cancer.
(2) The drugs should have different mechanisms of action.
(3) Cross-resistance between drugs should be minimal.
(4) The drugs should have different toxic effects
STRATEGIES IN CANCER CHEMOTHERAPY
C. RESCUE THERAPY
Toxic effects of anticancer drugs can be alleviated using rescue strategies. For example:
High doses of methotrexate are given for a short duration, then discontinued to prevent
severe toxicity to gastrointestinal tract and bone marrow cells.
Leucovorin is administered after methotrexate to rescue normal cells by bypassing a
critical step in folate synthesis.
Mercaptoethanesulfonate (mesna) traps acrolein released from cyclophosphamide,
reducing the risk of hemorrhagic cystitis.
Dexrazoxane inhibits free radical formation, protecting against cardiac toxicity induced
by anthracyclines like doxorubicin.
ALKYLATING AGENTS

The alkylating agents encompass several categories of drugs:

Nitrogen mustards: chlorambucil, cyclophosphamide, mechlorethamine
Nitrosoureas: carmustine, lomustine
Alkyl sulfonates: busulfan
Other agents with alkylating properties: cisplatin, dacarbazine,
The alkylating agents are cell cycle-nonspecific (CCNS) drugs. They create reactive
molecules that attach to nucleophilic sites on DNA bases,. This process causes cross-
linking between bases, abnormal pairing, and breakage of DNA strands. Tumor cells can
resist these drugs by enhancing DNA repair mechanisms, reducing drug entry into cells,
and producing substances that trap the drugs, like thiols.
ALKYLATING AGENTS
A. CYCLOPHOSPHAMIDE
1.Pharmacokinetics—Hepatic cytochrome P450 enzymes play a crucial role in the
biotransformation of cyclophosphamide, which is essential for its antitumor activity.
During this process, one of the breakdown products produced is acrolein.
2. Clinical use—Uses of cyclophosphamide include leukemia, non-Hodgkin’s
lymphoma, breast and ovarian cancers, and neuroblastoma.
3. Toxicity
Adverse effects: gastrointestinal distress, myelosuppression, and alopecia.
Hemorrhagic cystitis caused by acrolein formation can be reduced with hydration
and mesna.
Additional adverse effects: cardiac dysfunction, pulmonary toxicity, and syndrome
of inappropriate antidiuretic hormone (ADH) secretion.
ALKYLATING AGENTS
B. MECHLORETHAMINE
1. Mechanism and pharmacokinetics—Mechlorethamine spontaneously
converts in the body to a reactive cytotoxic product.
2. Clinical use—Mechlorethamine is best known for use in regimens for
Hodgkin’s and non-Hodgkin’s lymphoma.
3. Toxicity—Gastrointestinal distress, myelosuppression, alopecia, and sterility
are common. Mechlorethamine has marked vesicant (blister-forming) actions.
ALKYLATING AGENTS
C. PLATINUM ANALOGS (CISPLATIN, CARBOPLATIN, OXALIPLATIN)
. Pharmacokinetics—The platinum agents are used intravenously; the drugs distribute to most tissues
and are cleared in unchanged form by the kidney.
2. Clinical use—Cisplatin is commonly used as a component of regimens for testicular carcinoma and
for cancers of the bladder, lung, and ovary. Carboplatin has similar uses. Oxaliplatin is used in
advanced colon cancer.
3.Toxicity-
Cisplatin:
Causes gastrointestinal distress and mild hematotoxicity.
Neurotoxic
Nephrotoxic
Carboplatin:
Less nephrotoxic than cisplatin.
Less likely to cause tinnitus and hearing loss.
Greater myelosuppressant actions.
Oxaliplatin:
Causes dose-limiting neurotoxicity.
ALKYLATING AGENTS
D. PROCARBAZINE
1. Mechanisms—Procarbazine is a reactive agent that forms hydrogen peroxide, which generates
free radicals that cause DNA strand scission.
2. Pharmacokinetics—Procarbazine is orally active and penetrates into most tissues, including
the cerebrospinal fluid. It is eliminated via hepatic metabolism.
3. Clinical use—The primary use of the drug is as a component of regimens for Hodgkin’s and
non-Hodgkin’s lymphoma, and brain tumors.
4. Toxicity-
Procarbazine:
Myelosuppressant.
Causes gastrointestinal irritation.
CNS dysfunction and peripheral neuropathy.
Skin reactions.
Inhibits enzymes, including monoamine oxidase and hepatic drug metabolism.
Disulfiram-like reactions with ethanol.
Leukemogenic.
ALKYLATING AGENTS
E. OTHER ALKYLATING AGENTS
Busulfan:
Used in chronic myelogenous leukemia.
Causes adrenal insufficiency.
Leads to pulmonary fibrosis.
Causes skin pigmentation.
Carmustine and Lomustine:
Highly lipid-soluble drugs.
Used as adjuncts in brain tumor management.
Dacarbazine:
Used in Hodgkin’s lymphoma regimens.
Adverse effects:
Alopecia.
Skin rash.
Gastrointestinal distress.
Myelosuppression.
Phototoxicity.
Flu-like syndrome.
ANTIMETABOLITES
INTRODUCTION
Structurally similar to endogenous compounds.
Act as antagonists of:
Folic acid (methotrexate).
Purines (mercaptopurine, thioguanine).
Pyrimidines (fluorouracil, cytarabine, gemcitabine).
Mechanism of Action:
Act primarily in the S phase of the cell cycle.
Effects:
Cytotoxic effects on neoplastic cells.
Immunosuppressant actions.
ANTIMETABOLITES
A. METHOTREXATE
Mechanism of Action:
Inhibitor of dihydrofolate reductase.
Leads to:
Decrease in synthesis of thymidylate, purine nucleotides, and amino acids.
Interference with nucleic acid and protein metabolism.
Formation of polyglutamate derivatives of methotrexate is crucial for cytotoxic
actions.
. Tumor cell resistance mechanisms include decreased drug accumulation, changes
in the drug sensitivity or activity of dihydrofolate reductase, and decreased
formation of polyglutamates.
ANTIMETABOLITES
A. METHOTREXATE

Pharmacokinetics:
Oral and intravenous administration provides good tissue distribution except to the CNS.
Methotrexate is not metabolized.
Clearance is dependent on renal function.
Adequate hydration required to prevent crystallization in renal tubules
Clinical use:
Effective in:
Choriocarcinoma, Acute leukemias, Non-Hodgkin’s lymphomas, Primary central
nervous system lymphomas, Solid tumors like breast cancer, head and neck cancer,
and bladder cancer
Also used in:
Rheumatoid arthritis, Psoriasis, Ectopic pregnancy
ANTIMETABOLITES
A. METHOTREXATE
Toxicity:
Common adverse effects:
Bone marrow suppression
Toxic effects on the skin and gastrointestinal mucosa (mucositis)
Toxic effects may be reduced by administration of folic acid (leucovorin),
known as leucovorin rescue
Long-term use associated with:
Hepatotoxicity
ANTIMETABOLITES
B. MERCAPTOPURINE (6-MP) AND THIOGUANINE (6-TG)
Mechanisms of action and resistance:
Mercaptopurine and thioguanine are purine antimetabolites.
Activation: Both drugs are activated by hypoxanthine-guanine
phosphoribosyltransferases (HGPRTases) to toxic nucleotides.
Inhibition: Toxic nucleotides inhibit several enzymes involved in purine
metabolism.
Resistance mechanisms:
Decreased activity of HGPRTase in resistant tumor cells.
Increased production of alkaline phosphatases that inactivate the
toxic nucleotides.
ANTIMETABOLITES
B. MERCAPTOPURINE (6-MP) AND THIOGUANINE (6-TG)
2. Pharmacokinetics—Mercaptopurine and thioguanine have low oral
bioavailability because of first-pass metabolism by hepatic enzymes. The
metabolism of 6-MP by xanthine oxidase is inhibited by the xanthine
oxidase inhibitors allopurinol and febuxostat.
3. Clinical use—Purine antimetabolites are used mainly in the acute
leukemias and chronic myelocytic leukemia.
4. Toxicity—Bone marrow suppression is dose limiting, but hepatic
dysfunction also occurs
ANTIMETABOLITES
C. FLUOROURACIL (5-FU)
Mechanisms:
Fluorouracil is converted into 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-
FdUMP) in cells. This compound inhibits thymidylate synthase, leading to cell death
due to lack of thymine. Additionally, 5-FdUMP is incorporated into DNA, inhibiting
DNA synthesis and function. Another metabolite of fluorouracil, 5-fluorouridine-5′-
triphosphate (FUTP), is incorporated into RNA, interfering with RNA processing and
function.
Tumor cell resistance mechanisms:
Decreased activation of 5-FU.
Increased thymidylate synthase activity.
Reduced drug sensitivity of thymidylate synthase enzyme.
ANTIMETABOLITES
C. FLUOROURACIL (5-FU)
2. Pharmacokinetics—When given intravenously, fluorouracil is widely
distributed, including into the cerebrospinal fluid. Elimination is mainly by
metabolism.
3. Clinical use—Fluorouracil is used in bladder, breast, colon, anal, head and
neck, liver, and ovarian cancers.
4. Toxicity—Gastrointestinal distress, myelosuppression, and alopecia are
common
ANTIMETABOLITES
D. CYTARABINE (ARA-C)
Mechanisms of action and resistance:
Cytarabine (cytosine arabinoside):
Activation: The drug is activated by kinases to AraCTP (cytarabine
triphosphate).
Inhibition: AraCTP inhibits DNA polymerases.
Cell cycle specificity: Cytarabine is most specific for the S phase of the
cell cycle.
Resistance:
Decreased uptake: Resistance to cytarabine can occur due to reduced
cellular uptake of the drug.
Decreased conversion: Resistance may also result from decreased
conversion of cytarabine to AraCTP.
ANTIMETABOLITES
E. GEMCITABINE
Mechanisms:
Activation: Gemcitabine is converted into the active diphosphate and
triphosphate nucleotide form.
Inhibition: Gemcitabine diphosphate inhibits ribonucleotide reductase,
reducing the pool of deoxyribonucleoside triphosphates necessary for
DNA synthesis.
Incorporation: Gemcitabine triphosphate can be incorporated into DNA,
leading to chain termination.
ANTIMETABOLITES
E. GEMCITABINE
2. Pharmacokinetics—Elimination is mainly by metabolism.
3. Clinical use—Gemcitabine was initially approved for pancreatic cancer
and now is used widely in the treatment of non-small cell lung cancer,
bladder cancer, and non-Hodgkin’s lymphoma.
4. Toxicity—Primarily myelosuppression occurs, mainly as neutropenia.
Pulmonary toxicity has been observed.
NATURAL PRODUCT ANTICANCER DRUGS

Plant-derived CCS drugs:

Vinca alkaloids:
Examples: Vinblastine, Vincristine, Vinorelbine
Podophyllotoxins:
Examples: Etoposide, Teniposide
Camptothecins:
Examples: Topotecan, Irinotecan
Taxanes:
Examples: Paclitaxel, Docetaxel
NATURAL PRODUCT ANTICANCER DRUGS
A. VINBLASTINE, VINCRISTINE, AND VINORELBINE
1.Mechanisms:
The vinca alkaloids block the formation of the mitotic spindle by preventing the
assembly of tubulin dimers into microtubules.
They primarily act in the M phase of the cancer cell cycle.
Resistance can occur from increased efflux of the drugs from tumor cells via the
membrane drug transporter.
2. Pharmacokinetics—These drugs must be given parenterally. They penetrate most
tissues except the cerebrospinal fluid. They are cleared mainly via biliary excretion.
3. Clinical use—Vincristine is used in acute leukemias, lymphomas, Wilms’ tumor, and
neuroblastoma. Vinblastine is used for lymphomas, neuroblastoma, testicular
carcinoma, and Kaposi’s sarcoma. Vinorelbine is used in non-small cell lung cancer and
breast cancer
NATURAL PRODUCT ANTICANCER DRUGS
A. VINBLASTINE, VINCRISTINE, AND VINORELBINE
4. Toxicity—Vinblastine and vinorelbine cause gastrointestinal distress,
alopecia, and bone marrow suppression. Vincristine does not cause serious
myelosuppression but has neurotoxic actions and may cause areflexia,
peripheral neuritis, and paralytic ileus.
NATURAL PRODUCT ANTICANCER DRUGS
B. ETOPOSIDE AND TENIPOSIDE
Mechanisms:
Etoposide, a semisynthetic derivative of podophyllotoxin, induces DNA breakage
through its inhibition of topoisomerase II.
The drug is most active in the late S and early G2 phases of the cell cycle.
Teniposide is an analog with very similar pharmacologic characteristics.
2. Pharmacokinetics—Etoposide is well absorbed after oral administration and distributes
to most body tissues. Elimination of etoposide is mainly via the kidneys, and dose reductions
should be made in patients with renal impairment.
3. Clinical use—These agents are used in combination drug regimens for therapy of
lymphoma, and lung, germ cell, and gastric cancers.
4. Toxicity—Etoposide and teniposide are gastrointestinal irritants and cause alopecia and
bone marrow suppression.
NATURAL PRODUCT ANTICANCER DRUGS
C. TOPOTECAN AND IRINOTECAN
Mechanisms:
The two camptothecins, topotecan and irinotecan, produce DNA damage by inhibiting
topoisomerase I.
They damage DNA by inhibiting an enzyme that cuts and re-ligates single DNA strands
during normal DNA repair processes.

Pharmacokinetics:
Irinotecan is a prodrug converted in the liver into an active metabolite, SN-38.
Topotecan is eliminated renally, whereas irinotecan and its metabolite are eliminated in
the bile and feces.
Genetic variation significantly affects irinotecan metabolism, particularly in individuals
with variants of UGT1A that result in low glucuronidation activity, leading to excessive
toxicity.
NATURAL PRODUCT ANTICANCER DRUGS
C. TOPOTECAN AND IRINOTECAN
3. Clinical use—Topotecan is used as second-line therapy for advanced
ovarian cancer and for small cell lung cancer. Irinotecan is used for
metastatic colorectal cancer.
4. Toxicity—Myelosuppression and diarrhea are the 2 most common
toxicities.
NATURAL PRODUCT ANTICANCER DRUGS
D. PACLITAXEL AND DOCETAXEL
Mechanisms:
Paclitaxel and docetaxel interfere with the mitotic spindle.
Taxanes act differently from vinca alkaloids by preventing microtubule
disassembly into tubulin monomers.
2. Pharmacokinetics—Paclitaxel and docetaxel are given intravenously.
3. Clinical use—The taxanes have activity in a number of solid tumors, including
breast, ovarian, lung, gastroesophageal, prostate, bladder, and head and neck
cancers.
4. Toxicity
Paclitaxel: Neutropenia, thrombocytopenia, high incidence of peripheral
neuropathy, possible hypersensitivity reactions during infusion.
Docetaxel: Neurotoxicity, bone marrow depression.
ANTITUMOR ANTIBIOTICS

This category of antineoplastic drugs is made up of several structurally dissimilar

microbial products and includes the anthracyclines, bleomycin, and mitomycin.
A. Anthracyclines
Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone)
Mechanisms:
Intercalation between DNA base pairs
Inhibition of topoisomerase II
Generation of free radicals
Blockage of RNA and DNA synthesis
Induction of DNA strand scission
Membrane disruption
Anthracyclines are cell cycle-nonspecific (CCNS) drugs
ANTITUMOR ANTIBIOTICS
A. ANTHRACYCLINES
2. Pharmacokinetics—Doxorubicin and daunorubicin must be given intravenously. They are
metabolized in the liver, and the products are excreted in the bile and the urine.
3.Uses-
1. Doxorubicin:
Hodgkin’s and non-Hodgkin’s lymphoma, Myelomas, Sarcomas, Breast, lung, ovarian, and
thyroid cancers
2. Daunorubicin:
Treatment of acute leukemias
3. Idarubicin:
Acute myelogenous leukemia
4. Epirubicin:
Breast cancer, Gastroesophageal cancer
5. Mitoxantrone:
Acute myeloid leukemias, Non-Hodgkin’s lymphoma, Breast cancer, Gastroesophageal
cancer
ANTITUMOR ANTIBIOTICS
A. ANTHRACYCLINES
1. Bone marrow suppression
2. Gastrointestinal distress
3. Severe alopecia
4. Cardiotoxicity:
Initial electrocardiographic abnormalities
Possibility of arrhythmias
Slowly developing, dose-dependent cardiomyopathy and heart failure
5. Dexrazoxane:
Inhibitor of iron-mediated free radical generation, may protect against
dose-dependent cardiotoxicity
6. Liposomal formulations of doxorubicin may be less cardiotoxic.
ANTITUMOR ANTIBIOTICS
B. BLEOMYCIN
1. Mechanisms—Bleomycin is a mixture of glycopeptides that generates free
radicals, which bind to DNA, cause strand breaks, and inhibit DNA synthesis.
Bleomycin is a CCS drug active in the G2 phase of the tumor cell cycle.
2. Pharmacokinetics—Bleomycin must be given parenterally. It is inactivated by
tissue aminopeptidases, but some renal clearance of intact drug also occurs.
3. Clinical use—Bleomycin is a component of drug regimens for Hodgkin’s
lymphoma and testicular cancer. It is also used for treatment of lymphomas and
for squamous cell carcinomas.
ANTITUMOR ANTIBIOTICS
B. BLEOMYCIN
Pulmonary dysfunction:
Pneumonitis
Fibrosis
Slowly developing and dose-limiting
Hypersensitivity reactions:
Chills
Fever
Anaphylaxis
Common mucocutaneous reactions:
Alopecia
Blister formation
Hyperkeratosis
ANTITUMOR ANTIBIOTICS
C. MITOMYCIN
1. Mechanisms and pharmacokinetics—Mitomycin is a CCNS drug that is
metabolized by liver enzymes to form an alkylating agent that cross-links DNA.
Mitomycin is given intravenously and is rapidly cleared via hepatic metabolism.
2. Clinical use—Mitomycin acts against hypoxic tumor cells and is used in
combination regimens for adenocarcinomas of the cervix, stomach, pancreas, and
lung.
3. Toxicity—Mitomycin causes severe myelosuppression and is toxic to the heart,
liver, lung, and kidney.
MISCELLANEOUS ANTICANCER AGENTS
A. TYROSINE KINASE INHIBITORS
Selective Anticancer Drug: Imatinib
Target: Inhibits the tyrosine kinase activity of the protein product of the bcr-abl
oncogene
Associated Conditions: Commonly expressed in chronic myelogenous leukemia (CML)
associated with the Philadelphia chromosome translocation
Effectiveness: Effective for treatment of gastrointestinal stromal tumors expressing
the c-kit tyrosine kinase
Resistance Mechanism: Mutation of the bcr-abl gene
Toxicity:
Diarrhea
Myalgia
Fluid retention
Congestive heart failure
Newer Anticancer Kinase Inhibitors:
Dasatinib, Nilotinib, Bosutinib
MISCELLANEOUS ANTICANCER AGENTS
B. GROWTH FACTOR RECEPTOR INHIBITORS
1. Trastuzumab:
Type: Monoclonal antibody
Target: Recognizes surface protein overexpressed in breast cancer cells with HER-2/neu
receptor
Acute Toxicity:
Nausea and vomiting
Chills
Fevers
Headache
Cardiac Toxicity: May cause cardiac dysfunction, including heart failure
Drugs Inhibiting Epidermal Growth Factor Receptor (EGFR):
Role of EGFR: Regulates signaling pathways in cellular proliferation, invasion, metastasis,
and angiogenesis; implicated in inhibiting cytotoxic activity of some anticancer drugs and
radiation therapy.
MISCELLANEOUS ANTICANCER AGENTS
B. GROWTH FACTOR RECEPTOR INHIBITORS
2.Cetuximab:
Type: Chimeric monoclonal antibody
Target: Extracellular domain of EGFR
Uses:
Metastatic colon cancer (combination with irinotecan and oxaliplatin)
Head and neck cancer (combination with radiation)
Toxicity:
Skin rash
Hypersensitivity infusion reaction

3. Panitumumab:
Type: Fully human monoclonal antibody
Target: EGFR
Uses: Refractory metastatic colorectal cancer
MISCELLANEOUS ANTICANCER AGENTS
B. GROWTH FACTOR RECEPTOR INHIBITORS
4. Gefitinib and Erlotinib:
Type: Small molecule inhibitors of EGFR's tyrosine kinase domain
Uses:
Second-line agents for non-small cell lung cancer
Erlotinib: Combination therapy for advanced pancreatic cancer
Toxicity:
Rash, Diarrhea
5. Bevacizumab:
Type: Monoclonal antibody
Target: Binds to vascular endothelial growth factor (VEGF)
Mechanism: Prevents VEGF from interacting with VEGF receptors
Role: Inhibits angiogenesis required for tumor metastasis
Activity: Effective in colorectal, breast, non-small cell lung, and renal cancer
Adverse Effects:
Hypertension, Infusion reactions, Arterial thrombosis, Impaired wound healing,
Gastrointestinal perforation, Proteinuria
MISCELLANEOUS ANTICANCER AGENTS
B. GROWTH FACTOR RECEPTOR INHIBITORS
6. Ziv-aflibercept:
Mechanism: Interferes with VEGF function
Composition: Recombinant fusion protein of VEGF binding portions from extracellular
domains of human VEGF receptors 1 and 2, fused to the Fc portion of human IgG1
7. Sorafenib, Sunitinib, and Pazopanib:
Type: Small molecules
Targets: Multiple receptor tyrosine kinases (RTKs), including VEGF receptor family
Metabolism: Metabolized by CYP3A4
Elimination: Primarily hepatic
Adverse Effects:
Hypertension
Bleeding complications
Fatigue
MISCELLANEOUS ANTICANCER AGENTS
C. RITUXIMAB

Type: Monoclonal antibody

Targets: Surface protein in non-Hodgkin’s lymphoma cells
Mechanism of Action:
Induces complement-mediated lysis
Direct cytotoxicity
Induction of apoptosis
Current Use: Combined with conventional anticancer drugs (e.g.,
cyclophosphamide, vincristine, prednisone) in low-grade lymphomas
Adverse Effects:
Hypersensitivity reactions
Myelosuppression
MISCELLANEOUS ANTICANCER AGENTS
D. INTERFERONS
Type: Endogenous glycoproteins
Actions:
Antineoplastic
Immunosuppressive
Antiviral
Subtype: Alpha-interferons
Effectiveness: Against various neoplasms, including:
Hairy cell leukemia
Early stage of chronic myelogenous leukemia
T-cell lymphomas
Toxic Effects:
Myelosuppression
Neurologic dysfunction
MISCELLANEOUS ANTICANCER AGENTS
E. ASPARAGINASE
Function: Depletes serum asparagine
Use: Treatment of T-cell auxotrophic cancers (leukemia and
lymphomas) that require exogenous asparagine for growth
Administration: Intravenous
Adverse Effects:
Severe hypersensitivity reactions
Acute pancreatitis
Bleeding
MISCELLANEOUS ANTICANCER AGENTS
F. PROTEASOME INHIBITORS
Bortezomib and Carfilzomib:
Mechanism of Action: Inhibitors of the chymotrypsin-like activity of the 26S
proteasome in mammalian cells
Function of 26S Proteasome: Degrades ubiquitinated proteins, such as cyclin-
dependent kinases
Result of Inhibition: Down-regulation of the nuclear factor kappa B (NF-κB) signaling
pathway
Adverse Effects:
Peripheral neuropathy
Thrombocytopenia
Heart failure
Hypotension
Clinical Use: Treatment of multiple myeloma
HORMONAL ANTICANCER AGENTS
A. GLUCOCORTICOIDS
Prednisone is the most commonly used glucocorticoid in cancer chemotherapy and is widely
used in combination therapy for leukemias and lymphomas.
TOXICITY:
Metabolic Effects:
Growth inhibition, Diabetes, Muscle wasting, Osteoporosis
Other Toxicities:
Salt retention, Psychosis
Minimization Strategies:
Local application (e.g., aerosols for asthma)
Alternate-day therapy (to reduce pituitary suppression)
Tapering the dose soon after achieving a therapeutic response
Adrenal Insufficiency Prevention:
Administer additional "stress doses" during serious illness or major surgery
Withdrawal Management:
Taper doses slowly over several months to allow recovery of normal adrenal function
HORMONAL ANTICANCER AGENTS
B. GONADAL HORMONE ANTAGONISTS
1. Tamoxifen:
Mechanism: Selective estrogen receptor modulator (SERM)
Clinical Use: Receptor-positive breast carcinoma, prevention in high-risk women
Adverse Effects:
Endometrial hyperplasia and neoplasia (due to agonist activity), Nausea and
vomiting, Hot flushes, Vaginal bleeding, Venous thrombosis
2. Toremifene:
Type: Estrogen receptor antagonist
Use: Advanced breast cancer
3. Flutamide:
Type: Androgen receptor antagonist
Use: Prostatic carcinoma
Adverse Effects:
Gynecomastia, Hot flushes, Hepatic dysfunction
HORMONAL ANTICANCER AGENTS
C. GONADOTROPIN-RELEASING HORMONE (GNRH) ANALOGS
Leuprolide, Goserelin, Nafarelin:
Type: Gonadotropin-releasing hormone (GnRH) agonists
Effectiveness: Prostatic carcinoma
Mechanism: Inhibition of pituitary luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) release
Adverse Effects of Leuprolide:
Bone pain
Gynecomastia
Hematuria
Impotence
Testicular atrophy
HORMONAL ANTICANCER AGENTS
D. AROMATASE INHIBITORS
Anastrozole, Letrozole:
Mechanism: Inhibition of aromatase enzyme, blocking conversion of
androstenedione to estrone
Indication: Advanced breast cancer
Adverse Effects:
Nausea
Diarrhea
Hot flushes
Bone and back pain
Dyspnea
Peripheral edema