2. 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.
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3. 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
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4. 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.
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6. 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
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7. 7
▪ The alkylating agents are a class of drugs that are capable of introducing an alkyl group
▪ Contain an alkyl group (highly reactive chemical group which allow them to form
irreversible covalent bond with other molecules specially at the cross link of DNA).
▪ In DNA, the N-7 position of guanine is especially susceptible to alkylation, it interferes
with separation of the strands and prevent mitosis.
Alkylating agents
Common structure
8. 8
Alkylating agents Mechanism With Guanine Base
1- Attachment of the alkyl groups to DNA bases
2-Formation of cross bridges, bonds between atoms in the DNA.
3-Induction of mispairing of the nucleotides leading to mutations
Nitrogen Mustard
10. Nitrogen mustards
➢ 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
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11. ▪ 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.
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13. ▪ 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).
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14. ➢ 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
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15. ➢ 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
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16. Metabolic and chemical activation of cyclophosphamide
Toxic metabolite
Active
Inactive
In Liver
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17. 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
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18. Coadministration of Mesna is recommended with Cyclophosphamide
Detoxification of cyclophosphamide by Mesna
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19. ➢ 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.
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21. Alkyl Sulphonate
▪ 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
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➢ Busulfan
22. Structure of busulfan (alkyl alcane sulfonates) and of its mechanism of DNA or protein alkylation
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23. 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
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24. ▪ 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
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25. 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
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26. ➢ 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
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27. 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)
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28. Metabolic and chemical activation of procarbazine
Alkylation mainly takes place on O6 position of guanines
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29. ➢ 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 used to treat specific types of brain cancer (eg,
glioblastoma multiforme, anaplastic astrocytoma)
▪ 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
Imidazole carboxamide
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glioblastoma
30. Organoplatinum compounds
Platinum-containing antineoplastics
▪ These agents do not have an alkyl group, but they also damage DNA. They permanently coordinate to
DNA to interfere with DNA repair (they trigger apoptosis).
▪ • Platin is the only heavy metal compound in common use as a cancer chemotherapeutic agent
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31. ➢ Cisplatin (Cis-diaminedichloroplatinum):
▪ Cisplatin is available in 10- and 50-mg vials for IV administration in the treatment of a wide variety of cancers
including non-Hodgkin’s lymphoma, bladder cancer, ovarian cancer, testicular cancer, and cancers of the
head and neck.
▪ Compared with other platins, cisplatin is the most reactive and therefore the most effective in platinating
DNA.
▪ After IV administration, the agent is widely distributed, highly protein bound (90%), and concentrates in the
liver and kidney. The elimination of platinum from the blood is a slow process with a terminal elimination
half life of 5 to 10 days.
▪ The greater reactivity of cisplatin gives rise to significant toxicities compared with other platins. These
include dose-limiting nephrotoxicity, which normally presents as elevated blood urea nitrogen (BUN) and
creatinine.
▪ Amifostine: Reduction of incidence and severity of toxicities associated with cisplatin administration
▪ Sodium thiosulfate may be given to reduce the nephrotoxicity.
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32. Mechanism of cisplatin activation and formation of DNA adducts
▪ Cisplatin is administered to cancer patients by intravenous (i.v.) injection. Based on the insufficient stability of the drug in
aqueous media, the injection solutions are freshly prepared shortly before use.
▪ After administration of the agent to mammals, the dichloro species is maintained in the blood stream as a result of the
relatively high chloride concentration.
▪ It is generally agreed that the chloride of cisplatin leaves after it enters cells one chloro group is substituted by a water
molecule in a process known as aquation, and then the Pt center together with two non-leaving amines bind to nucleic
DNA to form Pt-DNA crosslinks.
▪ The most favorable position on DNA base to react with cisplatin is the N7 site of deoxyguanosine residue. Cisplatin forms
only one covalent bond with DNA at first, which is named as monofunctional Pt-DNA adduct. In a second reaction,
cisplatin reacts with a second guanine base, forming a crosslink on the DNA. If the Pt-bonded DNA bases are on the same
strand, the formed crosslinks are intrastrand; if the DNA bases are on two different strands, the formed crosslinks are
interstrand. Movement into the tumor cells is accomplished by passive diffusion or carrier mediated transport.
In Blood In Cell
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33. ➢ Amifostine active
▪ Amifostine (Ethyol) is a cytoprotective adjuvant used in cancer chemotherapy and radiotherapy involving DNA-binding
chemotherapeutic agents. Amifostine is an organic thiophosphate prodrug which is hydrolyzed in vivo by alkaline
phosphatase to the active cytoprotective thiol metabolite.
▪ Amifostine is used therapeutically to reduce the incidence of neutropenia-related fever and infection induced by DNA-
binding chemotherapeutic agents including alkylating agents (e.g. cyclophosphamide) and platinum-containing agents (e.g.
cisplatin).
▪ Indicated to reduce cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced
ovarian cancer.
▪ Amifostine was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer.
▪ Chemoprotection for cisplatin in the treatment of metastatic melanoma
▪ Chemoprotection for cyclophosphamide in the treatment of advanced ovarian carcinoma
▪ Amifostine protects against cisplatin-induced ototoxicity in children with average-risk medulloblastoma
▪ Amifostine is also indicated to reduce the incidence of xerostomia in patients undergoing radiotherapy for head and neck
cancer
▪ 910 mg/m² IV (15-minute infusion), 30 minutes before chemotherapy
▪ Mechanism of action: Inside cells, amifostine detoxifies reactive metabolites of platinum and alkylating agents,
as well as scavenges free radicals. Other possible effects include accelerated DNA repair, induction of cellular
hypoxia, inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. Amifostine
is believed to radioprotective normal tissue via Warburg-type effects
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