Chemotherapy
Chemotherapy
Chemotherapy
Group Members
Name of student Registration Number
BABIRYE SCOVIA 23/U/27829/HTP
MUTEGEKI ADOLF 22/U/20704/HTG
ERINEO TIBESIGWA 22/H/20716/HTG
Topic of discussion
•Cancer Chemotheray I: Cell cycle Kinetics, alkylating agents and
antimetabolites
• Current treatment guidelines for Kaposi sarcoma
Cancer Chemotherapy
Chemotherapy is a widely used medical treatment for
cancer, and it involves the use of drugs to destroy or
inhibit the growth of cancer cells.
Chemotherapy is a systemic treatment, meaning it
affects the entire body, and it is often used in
conjunction with other cancer treatments such as
surgery, radiation therapy, or immunotherapy
Cell cycle kinetics
• The cell cycle is a series of events that a cell undergoes as it prepares to
divide and eventually gives rise to two daughter cells.
• Cell cycle kinetics play a significant role in the design and effectiveness of
cancer chemotherapy.
• The cell cycle is divided into different phases, including
G1 (gap 1),
S (synthesis),
G2 (gap 2), and
M (mitosis).
Cells may also enter a non-dividing state called G0.
Chemotherapy agents often target rapidly dividing
cells, as these are more susceptible to the cytotoxic
effects of the drugs.
• G1 Phase: This is the phase where the cell prepares
for DNA synthesis. Cells in G1 are particularly
vulnerable to certain chemotherapy agents.
• S Phase: DNA synthesis occurs during this phase.
Agents that target DNA replication, such as
antimetabolites, are often effective during the S
phase.
• G2 Phase: The cell continues to grow and prepares
for mitosis.
Drugs affecting processes in G2 are also used in
chemotherapy.
• M Phase (Mitosis): This is the phase where cell
division occurs.
Agents targeting mitotic processes, such as
microtubule inhibitors, are utilized here.
• Cell cycle-nonspecific (CCNS) drug: An
anticancer agent that acts on tumor stem cells when
they are traversing the cell cycle and when they are
in the resting phase.
• Cell cycle-specific (CCS) drug: An anticancer
agent that acts selectively on tumor stem cells when
they are traversing the cell cycle and not when they
are in the G0 phase
• Growth fraction: The proportion of cells in a tumor
population that are actively dividing
• Myelosuppressant: A drug that suppresses the
formation of mature blood cells such as
erythrocytes, leukocytes, and platelets. This effect is
also known as “bone marrow suppression”
• Oncogene: A mutant form of a normal gene that is
found in naturally occurring tumors and which,
when expressed in noncancerous cells, causes them
to behave like cancer cells
Cancer Treatment Modalities
•Primary induction chemotherapy.
•Neoadjuvant chemotherapy.
•Adjuvant chemotherapy.
1. Primary induction chemotherapy—Drug therapy is administered
as the primary treatment for many hematologic cancers and for
advanced solid tumors for which no alternative treatment exists.
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.
Principles of Combination Therapy
• Chemotherapy with combinations of anticancer drugs usually increases
log-kill markedly, and in some cases synergistic effects are achieved.
• Drug combinations using CCS and CCNS drugs may be cytotoxic to
both dividing and resting cancer cells.
• The following principles are important for selecting appropriate drugs
to use in combination chemotherapy:
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
Rescue Therapy
• Toxic effects of anticancer drugs can sometimes be alleviated
by rescue strategy.
• For example, high doses of methotrexate may be given for
36–48 h to cells of the gastrointestinal tract and bone marrow
and terminated before severe toxicity occurs.
• Leucovorin, a form of tetrahydrofolate that is accumulated
more readily by normal than by neoplastic cells, is then
administered.
• This results in rescue of the normal cells because leucovorin
bypasses the dihydrofolate reductase step in folic acid
synthesis.
Alkylating agents
• Alkylating agents are a class of chemotherapy drugs that
are widely used in the treatment of cancer.
• These drugs work by adding alkyl groups to the DNA
molecule, leading to the formation of covalent bonds.
• This interference with DNA structure prevents the normal
functioning of DNA and ultimately results in cell death.
• Alkylating agents are considered cell cycle-nonspecific,
meaning they can affect cells in various phases of the cell
cycle.
Mechanism of Action
•Alkylating agents add alkyl groups to various cellular
components, with DNA being a primary target.
• They form reactive molecular species that alkylate nucleophilic
groups on DNA bases, particularly the N-7 position of guanine.
• This leads to cross-linking of bases, abnormal base-pairing, and
DNA strand breakage. Leading to the death of the cell
• Tumor cell resistance to the drugs occurs through increased
DNA repair, decreased drug permeability, and the production of
trapping agents such as thiols.
Types of Alkylating Agents
• Nitrogen Mustards: Examples include
cyclophosphamide, ifosfamide, and mechlorethamine.
• Nitrosoureas: Examples include carmustine,
lomustine, and streptozocin.
• Alkyl Sulfonates: Busulfan is an example of this class.
• Platinum Compounds: Cisplatin and carboplatin are
examples of platinum-based alkylating agents.
1. Cyclophosphamide
Formulation:
• Chemical Structure: Cyclophosphamide is a nitrogen mustard alkylating agent.
• Dosage Forms: It is commonly available in oral and intravenous formulations.
• Prodrug Activation: Requires enzymatic activation in the liver to form active
metabolites.
• Pharmacokinetics
• Absorption:
• Route: Well-absorbed orally.
• Bioavailability: High bioavailability but subject to significant first-pass metabolism.
• Time to Peak Concentration: Varied, with peak plasma concentrations achieved
within a few hours.
Metabolism
• Activation: Metabolized by hepatic cytochrome P450 enzymes to
form active metabolites, including 4-hydroxycyclophosphamide
and aldophosphamide.
• Acrolein Formation: Metabolism also yields acrolein, a metabolite
associated with toxicity.
Elimination:
• Excretion: Primarily excreted through the urine.
• Half-life: Short initial half-life; however, active metabolites
contribute to the prolonged therapeutic effect.
Clinical use
• Uses of cyclophosphamide include leukemia, non-Hodgkin’s
lymphoma, breast and ovarian cancers, and neuroblastoma.
• Mode of Action:
• Forming covalent bonds with DNA strands.
• Crosslinking DNA: Induces cross-linking within
DNA strands, disrupting DNA replication and
transcription.
• Cell Cycle Arrest: Results in cell cycle arrest and
apoptotic cell death.
• Immunosuppressive: Exhibits immunosuppressive
properties by affecting rapidly dividing cells,
including immune cells.
Toxicity
• Gastrointestinal Distress: Common adverse effect.
• Myelosuppression: Bone marrow suppression leading to
leukopenia and thrombocytopenia.
• Alopecia: Hair loss is an expected side effect.
• Hemorrhagic Cystitis: Risk of hemorrhagic cystitis due to
acrolein formation.
• Cardiac Dysfunction: Potential for cardiac toxicity.
• Pulmonary Toxicity: Adverse effects on the respiratory
system.
• Syndrome of Inappropriate ADH Secretion (SIADH): May
cause SIADH.
2. Mechlorethamine
Formulation
• Chemical Structure: Mechlorethamine, also known as mustine, is a nitrogen
mustard alkylating agent.
• Dosage Forms: Available in various formulations, including intravenous
solutions.
• Stability: Administered as a sterile solution due to instability in other forms.
Pharmacokinetics:
Absorption:
• Route: Primarily administered intravenously.
• Rapid Distribution: Rapid distribution to various tissues.
Metabolism:
• Rapid Inactivation: Quickly inactivated in the blood by reaction with plasma
proteins and other cellular components.
• Metabolites: May undergo metabolic transformation to various metabolites,
contributing to its therapeutic and toxic effects.
Elimination:
• Excretion: Mainly excreted through the urine.
• Short Half-Life: Exhibits a short half-life due to rapid inactivation.
Mode of Action:
• Acts as an alkylating agent by forming covalent bonds with DNA.
• Induces cross-linking within DNA strands, interfering with DNA replication and
transcription.
• Cell Cycle Arrest: Leads to cell cycle arrest and apoptotic cell death.
• Cytotoxic Effects: Disrupts rapidly dividing cells, including cancer cells.
Clinical use
• Uses of cyclophosphamide include leukemia, non-Hodgkin’s
lymphoma, breast and ovarian cancers, and neuroblastoma.
Toxicity:
• Hematologic Toxicity: Myelosuppression leading to leukopenia and
thrombocytopenia.
• Gastrointestinal Distress: Nausea, vomiting, and other
gastrointestinal symptoms.
• Dermatologic Effects: Skin rash and irritation at the injection site.
• Pulmonary Toxicity: Potential for respiratory complications.
• Secondary Malignancies: Risk of secondary malignancies due to the
alkylating nature of the drug.
3. Platinum Analogs (Cisplatin,
Carboplatin, Oxaliplatin):
Formulation
• Cisplatin:
• Intravenous: Typically administered as an intravenous infusion.
• Sterility: Must be prepared and administered under sterile conditions due to its
susceptibility to inactivation.
• Carboplatin:
• Intravenous: Administered intravenously, often as a solution.
• Aqueous Form: Unlike cisplatin, carboplatin is more stable in aqueous solutions.
• Oxaliplatin:
• Intravenous: Given through intravenous infusion.
• Compatibility: Requires protection from light during preparation due to photo-
instability.
Absorption
• Cisplatin:
• Limited Oral Bioavailability: Poor oral absorption; mainly
administered intravenously.
• Carboplatin:
• Exclusively administered intravenously.
• Rapidly distributed into tissues.
• Oxaliplatin:
• Intravenous Infusion: Administered intravenously as an
infusion.
• Distribution: Exhibits a large volume of distribution.
Metabolism:
• Cisplatin:
Undergoes minimal metabolism. Predominantly excreted unchanged through
the kidneys.
• Carboplatin:
Undergoes nonenzymatic hydrolysis in plasma. Renal Elimination: Renally
excreted.
• Oxaliplatin:
Undergoes limited metabolism. Excreted through both renal and biliary routes.
Mode of Action
• Form covalent bonds with DNA, leading to crosslinking.
• Interfere with DNA replication and transcription.
•Induce apoptosis in rapidly dividing cells, particularly cancer cells
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.
Toxicity
• Cisplatin causes gastrointestinal distress and mild hemotoxicity and is
neurotoxic (peripheral neuritis and acoustic nerve damage) and nephrotoxic.
• Renal damage may be reduced by the use of mannitol with forced
hydration.
• Carboplatin is less nephrotoxic than cisplatin and is less likely to cause
tinnitus and hearing loss, but it has greater myelosuppressant actions.
• Oxaliplatin causes dose-limiting neurotoxicity.
4. Procarbazine:
Formulation:
• Chemical Structure: Procarbazine is a hydrazine derivative.
• Oral Formulation: Typically formulated as an oral medication.
Absorption:
• Route: Administered orally. Well-absorbed from the gastrointestinal
tract.
Metabolism:
• Extensively metabolized in the liver. Metabolized into active
compounds, including isoniazid and acetaldehyde.
• Pharmacokinetics
• Procarbazine is orally active and penetrates into most tissues, including the
cerebrospinal fluid.
• It is eliminated via hepatic metabolism.
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.
Toxicity
• Procarbazine is a myelosuppressant and causes gastrointestinal irritation,
CNS dysfunction, peripheral neuropathy, and skin reactions. Procarbazine
inhibits many enzymes, including monoamine oxidase and those involved
in hepatic drug metabolism.
• Disulfiram-like reactions have occurred with ethanol. The drug is
leukemogenic.
Other Alkylating Agents
• Busulfan is sometimes used in chronic myelogenous
leukemia. It causes adrenal insufficiency, pulmonary
fibrosis, and skin pigmentation.
• Carmustine and lomustine are highly lipidsoluble drugs
used as adjuncts in the management of brain tumors.
• Dacarbazine is used in regimens for Hodgkin’s
lymphoma. It causes alopecia, skin rash, gastrointestinal
distress, myelosuppression, phototoxicity, and a flu-like
syndrome.
ANTIMETABOLITES
• Antimetabolites are a class of chemotherapeutic agents
that interfere with the normal cellular processes by
mimicking endogenous substances.
• These drugs disrupt vital metabolic pathways and are
commonly used in cancer treatment.
• They are CCS drugs acting primarily in the S phase of the
cell cycle. In addition to their cytotoxic effects on
neoplastic cells, the antimetabolites also have
immunosuppressant actions
1. Methotrexate
• 1. Mechanisms of action and resistance
Inhibition of Dihydrofolate Reductase (DHFR):
• Methotrexate competitively inhibits the enzyme DHFR, which is
essential for the conversion of dihydrofolate to tetrahydrofolate.
• This interference disrupts the synthesis of purines and pyrimidines,
essential components for DNA and RNA synthesis
• The formation of polyglutamate derivatives of methotrexate appears to
be important 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.
Pharmacokinetics
• Oral and intravenous administration of methotrexate affords good tissue distribution
except to the CNS. Methotrexate is not metabolized, and its clearance is dependent
on renal function. Adequate hydration is needed to prevent crystallization in renal
tubules.
Clinical use
• Methotrexate is effective in choriocarcinoma, acute leukemias, non-Hodgkin’s and
primary central nervous
Toxicity
• Common adverse effects of methotrexate include bone marrow suppression and
toxic effects on the skin and gastrointestinal mucosa (mucositis).
• The toxic effects of methotrexate on normal cells may be reduced by administration
of folinic (leucovorin); this strategy is called leucovorin rescue.
• Long-term use of methotrexate has led to hepatotoxicity and to pulmonary infiltrates
and fibrosis.
2. Mercaptopurine (6-MP) and Thioguanine (6-TG)
Mechanisms of action
• Fluorouracil is converted in cells to 5-fluoro-2-deoxyuridine-5-
monophosphate (5-FdUMP), which inhibits thymidylate synthase and
leads to “thymineless death” of cells.
• Incorporation of FdUMP into DNA inhibits DNA synthesis and function
while incorporation of 5-fluorouridine-5′-triphosphate (FUTP), another 5-
FU metabolite, into RNA interferes with RNA processing and function.
• Tumor cell resistance mechanisms include decreased activation of 5-FU,
increased thymidylate synthase activity, and reduced drug sensitivity of
this enzyme.
Pharmacokinetics
• When given intravenously, fluorouracil is widely distributed,
including into the cerebrospinal fluid.
• Elimination is mainly by metabolism.
Clinical use
• Fluorouracil is used in bladder, breast, colon, anal, head and
neck, liver, and ovarian cancers.
• The drug can be used topically for keratoses and superficial basal
cell carcinoma
Toxicity
• Gastrointestinal distress, myelosuppression, and alopecia are
common.
4. Cytarabine (ARA-C)
• 1. Mechanisms of action and resistance
• Cytarabine (cytosine arabinoside) is a pyrimidine
antimetabolite.
• The drug is activated by kinases to AraCTP, an inhibitor of
DNA
• polymerases.
• Of all the antimetabolites, cytarabine is the most specific for
the S phase of the cell cycle.
• Resistance to cytarabine can occur as a result of its decreased
uptake or its decreased conversion to AraCTP.
5. Gemcitabine
Mechanisms
• Gemcitabine is a deoxycytidine analog that is converted into the active
diphosphate and triphosphate nucleotide form.
• Gemcitabine diphosphate appears to inhibit ribonucleotide reductase
and thereby diminish the pool of deoxyribonucleoside triphosphates
required for DNA synthesis.
• Gemcitabine triphosphate can be incorporated into DNA, where it
causes chain termination.
Absorption:
• Route of Administration: Administered intravenously.
• Rapid Distribution: Rapidly distributed into tissues, including the
tumor
Pharmacokinetics
• Elimination is mainly by metabolism . Metabolites are primarily
excreted in the urine.
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.
Toxicity
• Primarily myelosuppression occurs, mainly as neutropenia.
• Pulmonary toxicity has been observed.
Current treatment guidelines for Kaposi
sarcoma
Kaposi's Sarcoma (KS) is a type of cancer that is caused by human
herpesvirus 8 (HHV-8) and is often seen in individuals with
compromised immune systems, such as those with HIV/AIDS.
The management of Kaposi's Sarcoma involves a combination o:-
• medical,
• surgical, and
• supportive care measures.
key aspects of managing Kaposi's Sarcoma:
1.Antiretroviral Therapy (ART):
• For individuals with HIV-associated Kaposi's Sarcoma, initiation and
maintenance of highly active antiretroviral therapy (ART) is crucial.
• Suppressing HIV replication helps improve the immune system's ability to
control HHV-8 and manage KS.
2.Chemotherapy:
• Chemotherapy, which involves the use of drugs to kill or slow down the
growth of cancer cells, is a common treatment for Kaposi's Sarcoma.
• The choice of chemotherapy drugs and regimens may vary based on the
extent of the disease and the overall health of the patient.
• Liposomal anthracyclines such as liposomal doxorubicin are often used
and have shown efficacy in treating KS.
3. Local Therapies:
Localized forms of KS, particularly those involving only a few lesions, may be treated
with local therapies.
This includes radiation therapy and intralesional chemotherapy.
4 Immune Reconstitution:
Improving immune function through antiretroviral therapy can lead to a reduction in the
severity of Kaposi's Sarcoma lesions.
Immune reconstitution is especially important in individuals with HIV-associated KS.
5. Supportive Care:
Supportive care measures focus on managing symptoms and improving the overall well-
being of the patient.
Pain management, wound care, and addressing psychological and emotional needs are
integral parts of supportive care for individuals with Kaposi's Sarcoma.
6. Monitoring and Follow-Up:
• Regular monitoring of the disease progression, response to treatment, and
potential side effects is essential.
• Follow-up appointments with healthcare providers, including dermatologists
and oncologists, help in adjusting treatment plans as needed.
7. Clinical Trials:
Participation in clinical trials may be considered, especially for patients with
advanced or refractory disease. Clinical trials provide access to new and
potentially more effective treatments.
8. Preventive Measures:
Preventive measures, such as sun protection and infection control practices, can
help minimize the risk of complications and infections in individuals with
Kaposi's Sarcoma.
• It's important to note that the management of Kaposi's
Sarcoma should be individualized based on:-
The patient's overall health,
The extent of the disease, and
Other specific factors.
• A multidisciplinary approach involving oncologists,
infectious disease specialists, and other healthcare
professionals is often employed to provide comprehensive
care.
• Patients should work closely with their healthcare team to
develop a personalized treatment plan.