Pyrimidine analogues: Cytarabine, Fluorouracil, and Related Drugs.

 Cytarabine is composed of cytosine and the sugar arabinose. The active triphosphate
metabolite of cytarabine blocks DNA synthesis by inhibition of DNA polymerase and
incorporation of the drug into nascent DNA, causing DNA chain termination.
 Cytarabine crosses the BBB and reaches CSF levels that are 40% to 50% of plasma levels.
 Fluorouracil is analogue of thymine in which the methyl group is replaced by a F atom.
Mechanism  Floxuridine is the deoxyribonucleoside derv. of fluorouracil
of action  Capecitabine is converted in the body to fluorouracil and its active metabolites.
Fluorouracil has two active metabolites:
1) 5-fluorodeoxyuridine monophosphate (5-FdUMP) and 5- fluorodeoxyuridine
triphosphate (5-FdUTP).
 5-FdUMP inhibits thymidylate synthetase and prevents the synthesis of thymidine, a major
building block of DNA.
 5-FdUTP is also incorporated into RNA by RNA polymerase and interferes with RNA
function.

Cytarabine and Fluorouracil

Uses  Cytarabine is used in combination with daunorubicin to treat acute myeloid
leukemia.
 Fluorouracil For solid tumors (breast, colorectal, and gastric carcinoma, and
squamous cell tumors of the head and neck) and liver metastasis.
 Topical for actinic keratoses and noninvasive skin cancers.
Toxicity 1) Nausea and vomiting, myelosuppression, oral and GI ulceration.
2) High doses can damage liver, heart, and other organs.
Uses and
side effects
Gemcitabine
Mechanism  It is an S-phase specific inhibitor of DNA synthesis, is a fluorinated
of action cytidine analogue.
 After conversion to gemcitabine diphosphate and triphosphate, these
metabolites inhibit the synthesis of DNA and DNA chain termination.
Uses 1) 1st line TTT for pancreatic carcinoma.
2) With Cisplatin as first-line therapy for non–small cell lung cancer.
 Biliary tract, gallbladder, breast, and ovarian cancer.
Side effects • Myelosuppression. ( Anemia, Leukopenia & thrombocytopenia.)
• Alopecia. • Various GI disturbances.

Ribonucleotide Reductase Inhibitor:

Hydroxyurea inhibits ribonucleotide reductase, that converts ribonucleotides to deoxyribonucleotides.
● It stops DNA synthesis and causes cells to accumulate in the S phase.
● It is given orally to treat chronic myelogenous leukemia, ovarian cancer, and melanoma.and also used in
the management of sickle cell anemia.
● In this condition, hydroxyurea elevates the Conc. of fetal hemoglobin and decreases the frequency of sickle
cell crises.
● The dose-limiting toxicity of hydroxyurea is rapid-onset myelosuppression.
 DNA alkylating agents:
 Most of them act to crosslink DNA strands by forming covalent bonds between alkyl groups of the drug
and guanine bases of DNA.
 A few alkylating drugs, as temozolomide, cause methylation of DNA but do not cross-link DNA strands.
 The DNA alkylating drugs include nitrogen mustards, nitrosourea drugs, and other agents.
 Platinum compounds (e.g., cisplatin) do not contain alkyl groups but cross-link DNA by forming
intrastrand and interstrand covalent bonds with DNA bases.

1) Nitrogen mustard
Mechanism of  Bifunctional alkylating agents, acting throughout the cell replication cycle, converted
action to active metabolites (electrophilic intermediates) in the liver which attack guanine bases
to form covalent bonds.
 This Cross-linking of DNA prevents replication and transcription.
1) Cyclophosphamide and Ifosfamide
 Prodrugs: converted to active alkylating metabolites by CYP450 enzymes (phosphoramide
mustard) & Acrolein that can cause hemorrhagic cystitis.
Indications:
Cyclophosphamide: Widely used because of its broad spectrum of activity;
 Acute and chronic lymphocytic leukemia.  Non-Hodgkin lymphoma
 Breast, lung, and ovarian cancers.
 Immunosuppressant, can be used in rheumatoid disorders and autoimmune nephritis.
 Preoperative regimens for BM transplantation.
Ifosfamide: Sarcoma, Testicular cancer
Adverse Effects:
Indications  Alopecia  Nausea, vomiting
&adverse  Myelosuppression, and Hemorrhagic cystitis (urinary irritation and blood loss from the
effects bladder).
 The dose-limiting toxicity of Cyclophosphamide is myelosuppression, while that of
Ifosfamide is usually hemorrhagic cystitis.
Mesna binds to and inactivate acrolein and can significantly reduce the incidence of cystitis.
2) Chlorambucil, Mechlorethamine, and Melphalan.
They are nitrogen mustards alkylating agents.
1) Chlorambucil:
 chronic lymphocytic leukemia( CLL).
 Can cause dose-limiting myelosuppression and sterility.
 Long-term therapy is associated with a high incidence of secondary acute leukemia.
2) Mechlorethamine: for TTT of Hodgkin and non-Hodgkin lymphomas.
3) Melphalan: For multiple myeloma (plasma cell myeloma) and breast cancer.
 Nitrosourea Drugs. Include Carmustine, Lomustine and Streptozocin.
Mechanism of  They spontaneously form active alkylating intermediates that cross-link DNA.
action  They are highly lipophilic and reach CSF .
Indications  Brain tumors, as astrocytomas.  Lymphomas
 Melanoma and multiple myeloma (Carmustine).
 Streptozocin is used only to treat pancreatic islet cell tumor (insulinoma).
Adverse effects  Delayed and prolonged myelosuppression, with complete recovery taking 6 to 8 weeks.
 Thrombocytopenia, nausea and vomiting.  Pulmonary damage with high doses.
Platinum compounds
Mechanism of  The drugs cisplatin, carboplatin, and oxaliplatin are inorganic platinum derivatives.
action  They are converted to active cytotoxic intermediate that react with guanine in DNA.
This leads to the formation of intra-strand crosslinks bet. neighboring guanine residues.
 The intra-strand links cause DNA to bend and distort the normal conformation of DNA
and impair its function.
Indications  Cisplatin: 1) 1st drug for TTT of testicular, ovarian, cervical, and bladder cancers
2) In melanoma and other solid tumors.
 Carboplatin: approved only for ovarian cancer.
 Oxaliplatin is used in ttt of advanced colon cancer.
Adverse effects  Cisplatin produces mild myelosuppression but can cause severe nausea, vomiting, and
nephrotoxicity.
Pretreatment with an antiemetic (e.g., ondansetron) is recommended
 The use of mannitol and sodium thiosulfate will decrease the severity of nephrotoxicity
 Mannitol increases urine flow and can reduce binding of cisplatin to renal tubule proteins.
 Sodium thiosulfate accumulates in renal tubules and neutralizes the cytotoxicity of
cisplatin.
Renal damage of cisplatin is often slowly reversible.

Other DNA Alkylating Drugs

 It’s a bifunctional alkylating agent, has greater activity against myeloid cells than
against lymphoid cells. It’s used for chronic myeloid leukemia (CML) ‫مهم‬
Adverse effects
Busulfan  Myelosuppression.
 Pulmonary fibrosis (“busulfan lung”):
 Has onset about 3 years after ttt begins,  No ttt has been successful.
 The average survival after diagnosis is 5 months.
 It is converted to active intermediates that can alkylate DNA, inhibiting DNA, RNA,
Dacarbazine and protein synthesis.
 Used for Hodgkin disease.
ABVD regimen: Adriamycin (doxorubicin), Bleomycin, Vinblastine, and Dacarbazine.
Mitomycin: (mitomycin C) is an antineoplastic antibiotic that alkylates DNA causing
strand breakage and inhibition of DNA synthesis.
Mitomycin  Used intravesically for bladder cancer.
and Temozolomide: It Methylates guanine residues of DNA, resulting in DNA damage and
Temozolomide tumor cell death. Used as a first-line drug for several brain tumors, including
astrocytoma and gliomas.
 DNA Intercalating Drugs: including Anthracyclines, bleomycin, and dactinomycin.
 Daunorubicin and doxorubicin are antibiotics obtained from a Streptomyces species.
 Idarubicin is a semisynthetic derivative.

Anthracyclines: Daunorubicin, Doxorubicin, and Idarubicin.

Mechanism of 1) Intercalation of DNA by inserting themselves bet. paired bases of double-stranded
action DNA so causing deformation and uncoiling of the DNA.
2) Inhibition of topoisomerase: cause DNA strands to break.
3) Formation of free radicals: cause DNA strands to break.
Indications  Daunorubicin and idarubicin: induction and consolidation therapy for acute myeloid
leukemia.
 Doxorubicin: breast cancer, Hodgkin disease, bladder cancer, ovarian cancer, and
other hematologic cancers and solid tumors
1) Myelosuppression
2) Cardiac damage (dose-limiting effects) due to free radicals formation:
sinus tachycardia and ventricular premature beats that could progress to congestive
cardiomyopathy.
Adverse effects 3) Nausea and vomiting 4) Alopecia; and mucosal ulcerations.
5) Extravasation of the drugs during IV infusion can lead to severe localized tissue
ulceration and necrosis.
-Measures to reduce cardiotoxicity:
 Dexrazoxane, potent chelator prevents reactive free radical formation (cardioprotective)
 Administer doxorubicin encapsulated in liposomes (Doxil)
Interactions  Verapamil can increase the cytotoxicity of doxorubicin and other anthracycline drugs.
 By inhibition of the (P glycoprotein) that transports anthracyclines out of cells.

Bleomycin
Chemistry &  It is a mixture of two peptides obtained from Streptomyces verticillus. its greatest
mechanism effect on neoplastic cells in the G 2 phase.
 Intercalates DNA .
 Iron-catalyzed free radical formation and DNA strand breakage.
Pharmacokinetics  It is inactivated in cells by aminohydrolase, whose low levels in skin and lung may
partly account for the toxicity of bleomycin in these tissues.
Indications  Hodgkin and non-Hodgkin lymphomas, testicular cancer, and other solid tumors.
 It is included in the ABVD regimen for Hodgkin disease.
Adverse Effects 1) Pulmonary: pneumonitis that progresses to interstitial fibrosis, hypoxia, and death.
● Monitor patients carefully for manifestations of pulmonary toxicity, which include
cough, dyspnea, rales, and pulmonary infiltrates noted on chest x-ray film.
2) Mucocutaneous reactions: mild stomatitis (inflammation of the oral mucosa),
skin hyperpigmentation, erythema, and edema.

Dactinomycin
1) Dactinomycin (actinomycin D) intercalates DNA.
2) Its use is limited for the ttt of 1] trophoblastic tumors, as choriocarcinoma.
2] pediatric tumors, as Wilms tumor and Ewing sarcoma.