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Anti-Cancer Drugs
(Part One)
Medicinal Chemistry IV / 2nd Semester / 4th Class
Lecture 3
Dr.Narmin Hamaamin Hussen
2021-2022
World Cancer Day on February 4
1
Introduction
▪Cancer is not a single disease . It is a group of more than 200
different diseases.
▪ Cancer may spread to other parts of the body.
▪ Currently 1 in 4 deaths in USA are due to cancer.
▪Iraqi cancer data for 2020 announced that there are over 33,837
cancer and tumor-related cases.
▪Cancer is considered one of the leading causes of mortality in Iraq,
contributing to an estimated 11% of total deaths.
2
Erbil and Duhok governorates’ cancer incidence stratified by gender (2013 to 2019)
Reference:DOI:10.31557/APJCP.2022.23.2.601 3
What is cancer?
▪ Cancer is characterized by an abnormal and uncontrolled,
division of cells, which produces tumours and invades adjacent
normal tissues.
▪ Often, cancer cells separate themselves from the primary
tumour, and are carried by the lymphatic system to reach
distant sites of the organs, where they divide and form
secondary tumours (metastasis).
▪ Apoptosis is the process of programmed cell death. It is used
during early development to eliminate unwanted cells.
Apoptosis also plays a role in preventing cancer.
4
Phases of the Cell Cycle
Regulation
5
Types of Tumors
Not all tumors are cancerous; tumors can be benign or malignant.
➢ Benign tumors aren't cancerous. They can often be removed, and, in most cases, they do
not come back. Cells in benign tumors do not spread to other parts of the body.
➢ Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and
spread to other parts of the body. The spread of cancer from one part of the body to
another is called metastasis
6
Stages of cancer
▪ Cancer staging is the process of determining the extent
to which a cancer has developed by growing and
spreading.
▪ There are several methods of staging including the
commonly used TNM system, where T—tumor, N—
lymph node involvement, and M—metastasis. In this
system, T and N are followed by numbers (1, 2, 3, etc.)
to indicate the size of the tumor and the extent of
lymph node involvement, respectively, where higher
numbers are associated with more advanced disease.
7
Causes and Risk factors
1.Environment
▪ cigarette smoke
▪ chemicals
▪ UV light
▪ viruses
2.Metabolic processes
▪ free radicals
▪ DNA copying and repair defects
3.Inherited genetic mutations
8
Cancer therapeutics modalities(classical)
9
The Classification of Anticancer Drugs According to chemical structure and
resource of the drug
1. Alkylating agents
2. Antimetabolites
3. Antibiotics
4. Plant products
5. Enzymes
6. Hormones
7. Immuno therapy
8. Monoclonal antibodies
9. Radio-therapeutic agents
10.Cyto-protective agents: Mesna, Amifostine, Dexrazoxane
11.Miscellaneous
10
Cell cycle specificity of Anti-Neoplastic agents
▪ Drugs that act during a specific phase of the cell
cycle
The Classification of Anticancer Drugs According to the cycle or phase
specificity of the drug
Cell cycle Non-specific agents
▪ Cell Cycle Nonspecific Agents (CCNSA) drugs
that are active throughout the cell cycle
➢ Alkylating Agents
➢ Platinum Compounds
➢ Antibiotics
11
I. Alkylating agents
a. Nitrogen mustards :Mechlorethamine, Ifosamide Cyclophosphamide, Melphalan ,Chlorambucil
b. Alkyl Sulphonate: Busulfan
c. Nitrosoureas : Carmustine, Lomustine, Semustine, Chlorozotocin
d. Aziridines : Thiotepa, Altretamine
e. Methylhydrazines: Procarbazine
f. Imidazole carboxamide: Dacarbazine ,Temozolomide
12
▪ The alkylating agents are a class of drugs that are capable of introducing an alkyl group into nucleophilic
sites on DNA , RNA or any enzyme through covalent bond .
▪ These compounds produce highly reactive carbonium ion intermediates that transfer alkyl group to cellular
macromolecules by forming covalent bond.
▪ These agents are thought to react with the n7 position of guanine ( or any other nitrogen base) in each of
the double strands of DNA, causing cross-linking that interferes with separation of the strands and prevents
mitosis. Blocks DNA synthesis
▪ Alkylation of DNA is thought to lead to cell death, although the exact mechanism is uncertain. Potential
mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the
template function of DNA.
Alkylating agents
Mechanism of action:
13
alkylating agents
Alkylation of guanine N-7 and subsequent depurination of DNA. 14
A- Nitrogen mustards
▪ Nitrogen mustards get their name because they are related to the sulfur-containing mustard gases used during
First world War. The term “mustard” comes from the similarity in the blisters produced by the compound and
those seen upon exposure to the oil of black mustard seeds.
▪ Nitrogen mustards contain bis(2-chloroethyl) group , modification of this group change stability , reactivity and
lipophilicity.
➢ Mechlorethamine(2-chloro-n-(2-chloroethyl)-n-methyl ethanamine)
▪ Is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for oral administration is
taken only by iv infusion(is available in 10-mg vials , direct injection into the tumor) and it used to treat
Hodgkin’s lymphoma and non-Hodgkin’s lymphoma
▪ A major disadvantage of mechlorethamine is that it has mutagenic and carcinogenic effect on bone marrow
stem cells(hemodynamic change),nausea, vomiting and skin toxicity.
CH3 . HCl
15
▪ Mustards such as mechlorethamine are classified as dialkylating agents in that one mustard molecule can
alkylate two nucleophiles.
▪ The initial acid– base reaction is necessary to release the lone pair of electrons on nitrogen, which
subsequently displaces chloride to give the highly reactive aziridinium cation.
▪ Nucleophilic attack can then occur at the aziridinium carbon to relieve the small ring strain and neutralize
the charge on nitrogen. This process can then be repeated provided a second leaving group is present
Alkylation of nucleophilic species by nitrogen mustards.
16
17
▪ Skin toxicity due to nitrogen mustard extravasation is
severe and typically prolonged over several months.
▪ Sodium thiosulfate is believed to chemically neutralize
reactive mechlorethamine-alkylating species and thus
decrease skin toxicity.
▪ Mechanism of action Neutralizes mechlorethamine to
form nontoxic thioesters that are excreted in the urine.
▪ In cases of extravasation (drug escapes from the
intravenous vein into the surrounding tissue, this can
cause local pain accompanied by burning or stinging,
blistering, erythema, swelling, and tenderness.), the
antidote sodium thiosulfate (Na2S2O3), a strong
nucleophile, may be administered. It is capable of
reacting with electrophilic sites on the mustard, and
once reaction has occurred, the resulting adduct has
increased water solubility and may be readily eliminated.
▪ Cancer patients are at an increased risk of extravasation
because of the fragility of their veins resulting from
radiation, previous chemotherapy treatments, or
malnutrition
Antidote of Mechlorethamine
Thiosulfate inactivation of mechlorethamine
✓ Inject 2 ml of the sodium thiosulfate solution for each
milligram of mechlorethamine suspected to have
extravasated. Inject the solution subcutaneously into
the extravasation site using a 25-gauge or smaller
needle (change needle with each injection).
18
➢ Chlorambucil and Melphalan
▪ The lack of selectivity of mechlorethamine led to attempts to improve on the agent. One rationale was to
reduce the reactivity by reducing the nucleophilicity of nitrogen, thereby slowing aziridinium cation
formation. This could be accomplished by replacement of the weakly electron-donating methyl group with
groups that were electron withdrawing
▪ This is seen in the case of chlorambucil and melphalan by attachment of nitrogen to a phenyl ring
➢ Chlorambucil
▪ Very slow acting
▪ Highly selective on lymphoid tissue ,very little effect on myeloid tissue
▪ Used in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma
▪ Suitable only for oral administration
➢ Melphalan
▪ Used in multiple myeloma, Ovarian cancer and Malignant melanoma
▪ Suitable for oral administration and Iv infusion
melanoma
19
➢ Cyclophosphamide:
▪ Cyclophosphamide is available in 25- and 50-mg tablets for oral administration and 100-, 200-, 500-, 1,000-,
and 2,000-mg vials for IV use
▪ Used in the treatment of a wide variety of cancers, including breast cancer, nonHodgkin’s lymphoma, chronic
lymphocytic leukemia, ovarian cancer, bone and soft tissue sarcoma.
▪ Also it has a potent immunosuppressant property
▪ This most widely used alkylating agent , it is inactive( Prodrug) in vitro but when it administered it is
metabolized by liver into phosphoramide mustard (active compound).
▪ In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in
cancer cells because they were believed to contain high levels of phosphoramidase enzymes. This would
remove the electron-withdrawing phosphoryl function and allow aziridine formation to occur.
▪ dehydrogenase
20
Metabolic and chemical activation of cyclophosphamide
Toxic metabolite
Active
Inactive
In Liver
21
Molecular Mechanisms of Acrolein Toxicity
▪ Acrolein-induced oxidative stress is associated with severe toxicity in the renal system due to
the use of anticancer agents such as cyclophosphamide and ifosfamide that get metabolized to
acrolein
Detoxification of Acrolein:
▪ MESNEX (Mesna) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by
cyclophosphamide or ifosfamide. The active ingredient, Mesna, is a synthetic sulfhydryl
compound designated as sodium-2-mercaptoethane sulfonate
▪ Acrolein toxicity is prevented by Mesna which binds with and clears acrolein.
▪ MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the
ifosfamide or cyclophosphamide dosage (w/w) at the time of ifosfamide or cyclophosphamide
administration.
▪ The recommended dose of oral Mesna is 40% of the cyclophosphamide or ifosfamide dose,
given prior to antineoplastic agents and then repeated at 2 hours and 6 hours after the
cyclophosphamide/ifosfamide dose
Adverse Effect of Cyclophosphamide (CP)
1- Hemorrhagic cystitis( inflammation urinary bladder) . A metabolite of CP, acrolein, is largely
responsible
2-Alopecia
Cyclophosphamide
Or Cyclophosphamide
Mesna
22
Coadministration of Mesna is recommended with Cyclophosphamide
Detoxification of cyclophosphamide by Mesna
23
➢ Ifosfamide (Iphosphamide, IFEX):
▪ Ifosfamide is available in 1- and 3-g vials for IV administration as Food and Drug Administration (FDA)-
approved third-line therapy in the treatment of testicular cancer.
▪ Also been utilized in the treatment of a wide variety of cancers including Hodgkin’s and non-Hodgkin’s
lymphoma, soft tissue sarcoma, germ cell tumors, small cell lung cancer, non–small cell lung cancer
(NSCLC), cancers of the head and neck, bladder cancer and cervical cancer.
▪ A synthetic analog of cyclophosphamide
Adverse effect: Hemorrhagic cystitis
▪ Coadministration of mesna is recommended.
▪ In contrast to cyclophosphamide, there is a greater amount of deactivation of the agent by N-
dechloroethylation and subsequently more chloroacetaldehyde is produced, which may result in a greater
amount of neurotoxicity and nephrotoxicity than seen with cyclophosphamide.
▪ Neurotoxicity, which is associated with the production of chloroacetaldehyde presents as confusion,
seizure, weakness, and hallucination, and coma may occur.
24
Metabolic and chemical activation of ifosfamide.
Toxic
Toxic
Toxic
Active
25
B- Alkyl Sulphonate
➢ Busulfan
▪ Busulfan is available as 2-mg tablets for oral administration and 10- mL for IV
administration
▪ Highly selective for myeloid elements (for granulocytes precursors than
platelets and red blood cell)
▪ Used in the treatment of chronic myelogenous leukemia (CML, a type of
cancer of the white blood cells) and in high-dose therapy for refractory
leukemia with bone marrow transplant.
▪ Busulfan is a bifunctional alkylan, a sulfonic acid alkyl ester,.
▪ Busulfan utilizes two sulfonate functionalities as leaving groups separated by
a four-carbon chain that reacts with DNA to primarily form intrastrand cross-
link at 5-GA-3 sequences
▪ The agent is well absorbed when given orally, well distributed into tissues,
and crosses the blood-brain barrier.
Adverse effect:
▪ Skin pigmentation
▪ Pulmonary fibrosis
▪ Hyperuricemia
CML
26
Structure of busulfan (alkyl alcane sulfonates) and of its mechanism of DNA or protein alkylation
27
C- Nitrosoureas
➢ Carmustine
▪ It has high lipid soluble
▪ It possesses the potential to cross the blood-brain-barrier, carmustine is employed specifically for brain tumours and other
tumours, for instance leukemias, which have metastasized to the brain. A combination of carmustine and prednisone is
used for the treatment of multiple myeloma. As a secondary therapy it is frequently employed in conjunction with other
antineoplastic agents for lymphomas and Hodgkin’s disease.
▪ The ‘drug’ most probably exerts its action due to the ability to cross-like cellular DNA. Thus the very synthesis of both DNA
and RNA is inhibited. It is specifically phase nonspecific.
➢ Lomustine
▪ It is employed effectively in the treatment of primary and metastatic brain tumours. It is also used as secondary therapy in
Hodgkin’s disease.
▪ Just like carmustine, it accomplishes maximum concentrations in the CSF choice status for the treatment of glioblastoma
Carmustine
28
▪ Their mechanism of action relies on the formation of diazohydroxyde
in basic conditions, that in turn generates a reactive cation responsible
for alkylation which takes place primarily on O6 or N7 positions of
guanines
▪ O6G alkylation by carmustine is described
▪ First, a chloroethylated adduct is generated and is followed by the
formation of a N1G:N3Cinter-strand cross-link
▪ This type of lesion contributes to the cytotoxicity of nitrosoureas to the
same extent than other cross-links such as O6G:N1C or N7G:N3C.
▪ Protein carbamoylation on lysine or arginine residues induced by
isocyanate could also impair the activity of key proteins involved in cell
survival such as DNA repair factors.
Adverse effect:
▪ Nausea and vomiting
▪ Bone marrow suppression
▪ Visceral fibrosis
▪ Renal damage
carmustine
29
D-Ethylenimine or Aziridine:
➢ Thiotepa (triethylenethiophosphoramide):
▪ Inactive drug (prodrug),
▪ Thiotepa is available in 15-mg vials for IV administration.
▪ Used in the treatment of bladder cancer, ovarian cancer, and breast cancer.
▪ High toxicity
▪ The ‘drug’ also crosses the blood-brain barrier (BBB)(neurotoxicity)
▪ Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients
receiving high-dose therapy(cutaneous toxicity in pediatric)
▪ Metabolism mediated by CYP2B1 and CYP2C11 effects desulfurization to give an active cytotoxic metabolite known as
Triethylene phosphoramide (TEPA) from which aziridine may arise. Aziridine metabolism occurs, with liberation of
ethanolamine.
Metabolic and chemical interactions of thiotepa with DNA
Active
cutaneous toxicity
30
➢ Altretamine
▪ Altretamine is available in 50-mg capsules for oral administration as a second-line treatment for
ovarian cancer.
▪ The mechanism of action has not been firmly established, although the spectrum of activity is
similar to that for other alkylating agents; however, cross-resistance is not seen.
▪ Cytotoxicity has been correlated with metabolism to give the carbinolamines, which may form
imines capable of crosslinking, or decompose to give formaldehyde, which may react with
nucleophiles on DNA or proteins.
▪ The agent is well absorbed upon oral administration, well distributed, and highly (90%) plasma
protein bound. The agent is extensively metabolized in the liver by CYP to give demethylated
metabolite via the previously mentioned carbinolamines
Altretamine
31
E- Methylhydrazines
➢ Procarbazine hydrochloride (PCZ):
▪ Procarbazine is available in 50-mg tablets for oral administration in the treatment of Hodgkin’s and brain cancer.
▪ The major mechanisms of resistance appear to be enhanced activity of DNA-repair enzymes including enhanced O-6-
alkylguanine DNA transferase (AGAT) which removes the methyl group from the O-6 of guanine.
▪ Chromosomal damage and also inhibiters of nucleic acid synthesis
▪ The agent is rapidly and completely absorbed after oral administration and extensively metabolized in the liver to give
azoprocarbazine followed by further oxidation to methyldiazine and the aldehyde. The parent drug and metabolites cross
the blood-brain barrier.
▪ Elimination occurs in the urine mostly as metabolites with an elimination half-life of 1 hour.
Adverse effect :
▪ Myelosuppression is dose limiting, generally presenting as thrombocytopenia that may be followed by leucopenia. Glucose-
6- phosphate dehydrogenase deficient patients may develop hemolytic anemia during procarbazine therapy.
▪ weak MAO inhibitors
▪ Sedation( pass BBB)
32
Metabolic and chemical activation of procarbazine
Alkylation mainly takes place on O6 position of guanines
33
➢ Dacarbazine (DTIC) and Temozolomide
▪ Dacarbazine also known as imidazole carboxamide, is a chemotherapy
medication used in the treatment of melanoma and Hodgkin's
lymphoma. For Hodgkin's it is often used together with vinblastine,
bleomycin, and doxorubicin. It is given by injection into a vein.
▪ Temozolomide is an imidazotetrazine derivative of the alkylating agent
dacarbazine.
▪ Temozolomide is not active but undergoes rapid nonenzymatic
conversion at physiologic pH to the reactive compound monomethyl 5-
triazino imidazole carboxamide (MTIC), which is also the active methyl
group–donating metabolite of DTIC.
▪ In contrast, MTIC is formed from dacarbazine only after metabolism by
the liver. Because hepatic metabolism can be influenced by agents
commonly taken by brain-tumor patients such as anticonvulsant
drugs and corticosteroids, it is thought that bioavailability of MTIC may
be more consistent with temozolomide than with dacarbazine. In
addition, temozolomide is administered orally and has strong capacity to
enter the cerebrospinal fluid without accumulation with repeat dosing,
further contributing to its rapidly developing clinical interest and
applications
O6 position of guanines
Temozolomide is used
to treat specific types
of brain cancer (eg,
glioblastoma
multiforme, anaplastic
astrocytoma)
F- Imidazole carboxamide
34
✓ What is the role of the p53 gene in cancer?
✓ What is the difference reaction mechanism between a carbonium
ions and carbanion?
35
36

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Anti-Cancer Drugs-Alkylating agents

  • 1. Anti-Cancer Drugs (Part One) Medicinal Chemistry IV / 2nd Semester / 4th Class Lecture 3 Dr.Narmin Hamaamin Hussen 2021-2022 World Cancer Day on February 4 1
  • 2. Introduction ▪Cancer is not a single disease . It is a group of more than 200 different diseases. ▪ Cancer may spread to other parts of the body. ▪ Currently 1 in 4 deaths in USA are due to cancer. ▪Iraqi cancer data for 2020 announced that there are over 33,837 cancer and tumor-related cases. ▪Cancer is considered one of the leading causes of mortality in Iraq, contributing to an estimated 11% of total deaths. 2
  • 3. Erbil and Duhok governorates’ cancer incidence stratified by gender (2013 to 2019) Reference:DOI:10.31557/APJCP.2022.23.2.601 3
  • 4. What is cancer? ▪ Cancer is characterized by an abnormal and uncontrolled, division of cells, which produces tumours and invades adjacent normal tissues. ▪ Often, cancer cells separate themselves from the primary tumour, and are carried by the lymphatic system to reach distant sites of the organs, where they divide and form secondary tumours (metastasis). ▪ Apoptosis is the process of programmed cell death. It is used during early development to eliminate unwanted cells. Apoptosis also plays a role in preventing cancer. 4
  • 5. Phases of the Cell Cycle Regulation 5
  • 6. Types of Tumors Not all tumors are cancerous; tumors can be benign or malignant. ➢ Benign tumors aren't cancerous. They can often be removed, and, in most cases, they do not come back. Cells in benign tumors do not spread to other parts of the body. ➢ Malignant tumors are cancerous. Cells in these tumors can invade nearby tissues and spread to other parts of the body. The spread of cancer from one part of the body to another is called metastasis 6
  • 7. Stages of cancer ▪ Cancer staging is the process of determining the extent to which a cancer has developed by growing and spreading. ▪ There are several methods of staging including the commonly used TNM system, where T—tumor, N— lymph node involvement, and M—metastasis. In this system, T and N are followed by numbers (1, 2, 3, etc.) to indicate the size of the tumor and the extent of lymph node involvement, respectively, where higher numbers are associated with more advanced disease. 7
  • 8. Causes and Risk factors 1.Environment ▪ cigarette smoke ▪ chemicals ▪ UV light ▪ viruses 2.Metabolic processes ▪ free radicals ▪ DNA copying and repair defects 3.Inherited genetic mutations 8
  • 10. The Classification of Anticancer Drugs According to chemical structure and resource of the drug 1. Alkylating agents 2. Antimetabolites 3. Antibiotics 4. Plant products 5. Enzymes 6. Hormones 7. Immuno therapy 8. Monoclonal antibodies 9. Radio-therapeutic agents 10.Cyto-protective agents: Mesna, Amifostine, Dexrazoxane 11.Miscellaneous 10
  • 11. Cell cycle specificity of Anti-Neoplastic agents ▪ Drugs that act during a specific phase of the cell cycle The Classification of Anticancer Drugs According to the cycle or phase specificity of the drug Cell cycle Non-specific agents ▪ Cell Cycle Nonspecific Agents (CCNSA) drugs that are active throughout the cell cycle ➢ Alkylating Agents ➢ Platinum Compounds ➢ Antibiotics 11
  • 12. I. Alkylating agents a. Nitrogen mustards :Mechlorethamine, Ifosamide Cyclophosphamide, Melphalan ,Chlorambucil b. Alkyl Sulphonate: Busulfan c. Nitrosoureas : Carmustine, Lomustine, Semustine, Chlorozotocin d. Aziridines : Thiotepa, Altretamine e. Methylhydrazines: Procarbazine f. Imidazole carboxamide: Dacarbazine ,Temozolomide 12
  • 13. ▪ The alkylating agents are a class of drugs that are capable of introducing an alkyl group into nucleophilic sites on DNA , RNA or any enzyme through covalent bond . ▪ These compounds produce highly reactive carbonium ion intermediates that transfer alkyl group to cellular macromolecules by forming covalent bond. ▪ These agents are thought to react with the n7 position of guanine ( or any other nitrogen base) in each of the double strands of DNA, causing cross-linking that interferes with separation of the strands and prevents mitosis. Blocks DNA synthesis ▪ Alkylation of DNA is thought to lead to cell death, although the exact mechanism is uncertain. Potential mechanisms of cell death include activation of apoptosis caused by p53 activation and disruption of the template function of DNA. Alkylating agents Mechanism of action: 13
  • 14. alkylating agents Alkylation of guanine N-7 and subsequent depurination of DNA. 14
  • 15. A- Nitrogen mustards ▪ Nitrogen mustards get their name because they are related to the sulfur-containing mustard gases used during First world War. The term “mustard” comes from the similarity in the blisters produced by the compound and those seen upon exposure to the oil of black mustard seeds. ▪ Nitrogen mustards contain bis(2-chloroethyl) group , modification of this group change stability , reactivity and lipophilicity. ➢ Mechlorethamine(2-chloro-n-(2-chloroethyl)-n-methyl ethanamine) ▪ Is highly reactive, in fact, too reactive and therefore nonselective, making it unsuitable for oral administration is taken only by iv infusion(is available in 10-mg vials , direct injection into the tumor) and it used to treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma ▪ A major disadvantage of mechlorethamine is that it has mutagenic and carcinogenic effect on bone marrow stem cells(hemodynamic change),nausea, vomiting and skin toxicity. CH3 . HCl 15
  • 16. ▪ Mustards such as mechlorethamine are classified as dialkylating agents in that one mustard molecule can alkylate two nucleophiles. ▪ The initial acid– base reaction is necessary to release the lone pair of electrons on nitrogen, which subsequently displaces chloride to give the highly reactive aziridinium cation. ▪ Nucleophilic attack can then occur at the aziridinium carbon to relieve the small ring strain and neutralize the charge on nitrogen. This process can then be repeated provided a second leaving group is present Alkylation of nucleophilic species by nitrogen mustards. 16
  • 17. 17
  • 18. ▪ Skin toxicity due to nitrogen mustard extravasation is severe and typically prolonged over several months. ▪ Sodium thiosulfate is believed to chemically neutralize reactive mechlorethamine-alkylating species and thus decrease skin toxicity. ▪ Mechanism of action Neutralizes mechlorethamine to form nontoxic thioesters that are excreted in the urine. ▪ In cases of extravasation (drug escapes from the intravenous vein into the surrounding tissue, this can cause local pain accompanied by burning or stinging, blistering, erythema, swelling, and tenderness.), the antidote sodium thiosulfate (Na2S2O3), a strong nucleophile, may be administered. It is capable of reacting with electrophilic sites on the mustard, and once reaction has occurred, the resulting adduct has increased water solubility and may be readily eliminated. ▪ Cancer patients are at an increased risk of extravasation because of the fragility of their veins resulting from radiation, previous chemotherapy treatments, or malnutrition Antidote of Mechlorethamine Thiosulfate inactivation of mechlorethamine ✓ Inject 2 ml of the sodium thiosulfate solution for each milligram of mechlorethamine suspected to have extravasated. Inject the solution subcutaneously into the extravasation site using a 25-gauge or smaller needle (change needle with each injection). 18
  • 19. ➢ Chlorambucil and Melphalan ▪ The lack of selectivity of mechlorethamine led to attempts to improve on the agent. One rationale was to reduce the reactivity by reducing the nucleophilicity of nitrogen, thereby slowing aziridinium cation formation. This could be accomplished by replacement of the weakly electron-donating methyl group with groups that were electron withdrawing ▪ This is seen in the case of chlorambucil and melphalan by attachment of nitrogen to a phenyl ring ➢ Chlorambucil ▪ Very slow acting ▪ Highly selective on lymphoid tissue ,very little effect on myeloid tissue ▪ Used in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma ▪ Suitable only for oral administration ➢ Melphalan ▪ Used in multiple myeloma, Ovarian cancer and Malignant melanoma ▪ Suitable for oral administration and Iv infusion melanoma 19
  • 20. ➢ Cyclophosphamide: ▪ Cyclophosphamide is available in 25- and 50-mg tablets for oral administration and 100-, 200-, 500-, 1,000-, and 2,000-mg vials for IV use ▪ Used in the treatment of a wide variety of cancers, including breast cancer, nonHodgkin’s lymphoma, chronic lymphocytic leukemia, ovarian cancer, bone and soft tissue sarcoma. ▪ Also it has a potent immunosuppressant property ▪ This most widely used alkylating agent , it is inactive( Prodrug) in vitro but when it administered it is metabolized by liver into phosphoramide mustard (active compound). ▪ In the case of cyclophosphamide, it was initially believed that the drug could be selectively activated in cancer cells because they were believed to contain high levels of phosphoramidase enzymes. This would remove the electron-withdrawing phosphoryl function and allow aziridine formation to occur. ▪ dehydrogenase 20
  • 21. Metabolic and chemical activation of cyclophosphamide Toxic metabolite Active Inactive In Liver 21
  • 22. Molecular Mechanisms of Acrolein Toxicity ▪ Acrolein-induced oxidative stress is associated with severe toxicity in the renal system due to the use of anticancer agents such as cyclophosphamide and ifosfamide that get metabolized to acrolein Detoxification of Acrolein: ▪ MESNEX (Mesna) is a detoxifying agent to inhibit the hemorrhagic cystitis induced by cyclophosphamide or ifosfamide. The active ingredient, Mesna, is a synthetic sulfhydryl compound designated as sodium-2-mercaptoethane sulfonate ▪ Acrolein toxicity is prevented by Mesna which binds with and clears acrolein. ▪ MESNEX injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide or cyclophosphamide dosage (w/w) at the time of ifosfamide or cyclophosphamide administration. ▪ The recommended dose of oral Mesna is 40% of the cyclophosphamide or ifosfamide dose, given prior to antineoplastic agents and then repeated at 2 hours and 6 hours after the cyclophosphamide/ifosfamide dose Adverse Effect of Cyclophosphamide (CP) 1- Hemorrhagic cystitis( inflammation urinary bladder) . A metabolite of CP, acrolein, is largely responsible 2-Alopecia Cyclophosphamide Or Cyclophosphamide Mesna 22
  • 23. Coadministration of Mesna is recommended with Cyclophosphamide Detoxification of cyclophosphamide by Mesna 23
  • 24. ➢ Ifosfamide (Iphosphamide, IFEX): ▪ Ifosfamide is available in 1- and 3-g vials for IV administration as Food and Drug Administration (FDA)- approved third-line therapy in the treatment of testicular cancer. ▪ Also been utilized in the treatment of a wide variety of cancers including Hodgkin’s and non-Hodgkin’s lymphoma, soft tissue sarcoma, germ cell tumors, small cell lung cancer, non–small cell lung cancer (NSCLC), cancers of the head and neck, bladder cancer and cervical cancer. ▪ A synthetic analog of cyclophosphamide Adverse effect: Hemorrhagic cystitis ▪ Coadministration of mesna is recommended. ▪ In contrast to cyclophosphamide, there is a greater amount of deactivation of the agent by N- dechloroethylation and subsequently more chloroacetaldehyde is produced, which may result in a greater amount of neurotoxicity and nephrotoxicity than seen with cyclophosphamide. ▪ Neurotoxicity, which is associated with the production of chloroacetaldehyde presents as confusion, seizure, weakness, and hallucination, and coma may occur. 24
  • 25. Metabolic and chemical activation of ifosfamide. Toxic Toxic Toxic Active 25
  • 26. B- Alkyl Sulphonate ➢ Busulfan ▪ Busulfan is available as 2-mg tablets for oral administration and 10- mL for IV administration ▪ Highly selective for myeloid elements (for granulocytes precursors than platelets and red blood cell) ▪ Used in the treatment of chronic myelogenous leukemia (CML, a type of cancer of the white blood cells) and in high-dose therapy for refractory leukemia with bone marrow transplant. ▪ Busulfan is a bifunctional alkylan, a sulfonic acid alkyl ester,. ▪ Busulfan utilizes two sulfonate functionalities as leaving groups separated by a four-carbon chain that reacts with DNA to primarily form intrastrand cross- link at 5-GA-3 sequences ▪ The agent is well absorbed when given orally, well distributed into tissues, and crosses the blood-brain barrier. Adverse effect: ▪ Skin pigmentation ▪ Pulmonary fibrosis ▪ Hyperuricemia CML 26
  • 27. Structure of busulfan (alkyl alcane sulfonates) and of its mechanism of DNA or protein alkylation 27
  • 28. C- Nitrosoureas ➢ Carmustine ▪ It has high lipid soluble ▪ It possesses the potential to cross the blood-brain-barrier, carmustine is employed specifically for brain tumours and other tumours, for instance leukemias, which have metastasized to the brain. A combination of carmustine and prednisone is used for the treatment of multiple myeloma. As a secondary therapy it is frequently employed in conjunction with other antineoplastic agents for lymphomas and Hodgkin’s disease. ▪ The ‘drug’ most probably exerts its action due to the ability to cross-like cellular DNA. Thus the very synthesis of both DNA and RNA is inhibited. It is specifically phase nonspecific. ➢ Lomustine ▪ It is employed effectively in the treatment of primary and metastatic brain tumours. It is also used as secondary therapy in Hodgkin’s disease. ▪ Just like carmustine, it accomplishes maximum concentrations in the CSF choice status for the treatment of glioblastoma Carmustine 28
  • 29. ▪ Their mechanism of action relies on the formation of diazohydroxyde in basic conditions, that in turn generates a reactive cation responsible for alkylation which takes place primarily on O6 or N7 positions of guanines ▪ O6G alkylation by carmustine is described ▪ First, a chloroethylated adduct is generated and is followed by the formation of a N1G:N3Cinter-strand cross-link ▪ This type of lesion contributes to the cytotoxicity of nitrosoureas to the same extent than other cross-links such as O6G:N1C or N7G:N3C. ▪ Protein carbamoylation on lysine or arginine residues induced by isocyanate could also impair the activity of key proteins involved in cell survival such as DNA repair factors. Adverse effect: ▪ Nausea and vomiting ▪ Bone marrow suppression ▪ Visceral fibrosis ▪ Renal damage carmustine 29
  • 30. D-Ethylenimine or Aziridine: ➢ Thiotepa (triethylenethiophosphoramide): ▪ Inactive drug (prodrug), ▪ Thiotepa is available in 15-mg vials for IV administration. ▪ Used in the treatment of bladder cancer, ovarian cancer, and breast cancer. ▪ High toxicity ▪ The ‘drug’ also crosses the blood-brain barrier (BBB)(neurotoxicity) ▪ Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy(cutaneous toxicity in pediatric) ▪ Metabolism mediated by CYP2B1 and CYP2C11 effects desulfurization to give an active cytotoxic metabolite known as Triethylene phosphoramide (TEPA) from which aziridine may arise. Aziridine metabolism occurs, with liberation of ethanolamine. Metabolic and chemical interactions of thiotepa with DNA Active cutaneous toxicity 30
  • 31. ➢ Altretamine ▪ Altretamine is available in 50-mg capsules for oral administration as a second-line treatment for ovarian cancer. ▪ The mechanism of action has not been firmly established, although the spectrum of activity is similar to that for other alkylating agents; however, cross-resistance is not seen. ▪ Cytotoxicity has been correlated with metabolism to give the carbinolamines, which may form imines capable of crosslinking, or decompose to give formaldehyde, which may react with nucleophiles on DNA or proteins. ▪ The agent is well absorbed upon oral administration, well distributed, and highly (90%) plasma protein bound. The agent is extensively metabolized in the liver by CYP to give demethylated metabolite via the previously mentioned carbinolamines Altretamine 31
  • 32. E- Methylhydrazines ➢ Procarbazine hydrochloride (PCZ): ▪ Procarbazine is available in 50-mg tablets for oral administration in the treatment of Hodgkin’s and brain cancer. ▪ The major mechanisms of resistance appear to be enhanced activity of DNA-repair enzymes including enhanced O-6- alkylguanine DNA transferase (AGAT) which removes the methyl group from the O-6 of guanine. ▪ Chromosomal damage and also inhibiters of nucleic acid synthesis ▪ The agent is rapidly and completely absorbed after oral administration and extensively metabolized in the liver to give azoprocarbazine followed by further oxidation to methyldiazine and the aldehyde. The parent drug and metabolites cross the blood-brain barrier. ▪ Elimination occurs in the urine mostly as metabolites with an elimination half-life of 1 hour. Adverse effect : ▪ Myelosuppression is dose limiting, generally presenting as thrombocytopenia that may be followed by leucopenia. Glucose- 6- phosphate dehydrogenase deficient patients may develop hemolytic anemia during procarbazine therapy. ▪ weak MAO inhibitors ▪ Sedation( pass BBB) 32
  • 33. Metabolic and chemical activation of procarbazine Alkylation mainly takes place on O6 position of guanines 33
  • 34. ➢ Dacarbazine (DTIC) and Temozolomide ▪ Dacarbazine also known as imidazole carboxamide, is a chemotherapy medication used in the treatment of melanoma and Hodgkin's lymphoma. For Hodgkin's it is often used together with vinblastine, bleomycin, and doxorubicin. It is given by injection into a vein. ▪ Temozolomide is an imidazotetrazine derivative of the alkylating agent dacarbazine. ▪ Temozolomide is not active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound monomethyl 5- triazino imidazole carboxamide (MTIC), which is also the active methyl group–donating metabolite of DTIC. ▪ In contrast, MTIC is formed from dacarbazine only after metabolism by the liver. Because hepatic metabolism can be influenced by agents commonly taken by brain-tumor patients such as anticonvulsant drugs and corticosteroids, it is thought that bioavailability of MTIC may be more consistent with temozolomide than with dacarbazine. In addition, temozolomide is administered orally and has strong capacity to enter the cerebrospinal fluid without accumulation with repeat dosing, further contributing to its rapidly developing clinical interest and applications O6 position of guanines Temozolomide is used to treat specific types of brain cancer (eg, glioblastoma multiforme, anaplastic astrocytoma) F- Imidazole carboxamide 34
  • 35. ✓ What is the role of the p53 gene in cancer? ✓ What is the difference reaction mechanism between a carbonium ions and carbanion? 35
  • 36. 36