This document discusses anticancer drugs, focusing on cyclophosphamide. It provides details on the classification and mechanisms of anticancer drugs, including cytotoxic drugs like alkylating agents. Cyclophosphamide is described as a bifunctional alkylating agent used to treat various cancers. Its pharmacokinetics, indications, side effects, dosing, and formulations are summarized. The structure-activity relationship of alkylating agents including cyclophosphamide is also reviewed.

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Anti-cancer drugs
Anticancer agents are chemical substances that inhibit or kill proliferating cancer cells, while
leaving host cells unharmed, or at least recoverable. Cancer is one of the major causes of
death and one of the most feared of diseases.
Cancer chemotherapy may consist of using several drugs in combination for varying lengths
of time because cancerous cells which are initially suppressed by a specific drug may develop
a resistance to that drug.Unfortunately, most of the chemicals that have been found to be
successful anti-cancer agents are extremely toxic and must be administered very carefully.
There are three goals associated with the use of the most commonly-used anticancer agents-
1. Damage the DNA of the affected cancer cells.
2. Inhibit the synthesis of new DNA strands to stop the cell from replicating, because
the replication of the cell is what allows the tumor to grow.
3. Stop mitosis or the actual splitting of the original cell into two new cells. Stopping
mitosis stops cell division (replication) of the cancer and may ultimately halt the progression
of the cancer.
Classification of drugs used in cancer chemotherapy
The main anticancer drugs can be divided into the following general categories.
A).Cytotoxic drugs. they include:
1.alkylating agents and related compounds: which act by forming covalent bonds with
DNA and thus impeding replication
 cyclophosphamide
 Cisplatin
 Chlorambucil
 Carmustine
 Lomustine
2.Antimetabolites: which block or subvert one or more of the metabolic pathways involved in
DNA synthesis
a)Folate antagonists: Methotrexate
b) Pyrimidine analogues: Fluorouracil, Cytarabine
c) Purine analogues: Mercaptopurine, Pentostatin
3.Natural Products:
a).Cytotoxic antibiotics: substances of microbial origin that prevent mammalian cell
division(by causing intercalation)
 Doxorubicin
 Bleomycin

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 Dactinomycin
 Mitomycin
b)Vinca alkaloids: Vinblastin, Vincristine
c) Epipodophylotoxin: Etoposide,Teniposide
d) Enzymes: L-Asparaginase
B).Hormones
1.Adrenocorticoids: Prednisone for leukaemias and lymphomas
2.Antiestrogen:Tamoxifen for breast tumours
3.Gonadotrophin-releasing hormone analogues: Leuprolide for prostate and breast tumours
4.Antiandrogens: Flutamide for prostate cancer
5.Estrogens:Diethylstilbestrol, Etinyl estradiol
C).Miscellaneous agents that do not fit into the above categories. This group includes a number of
recently developed drugs designed to affect specific tumour-related targets.
 Procarbazine: inhibits DNA and RNA synthesis and interferes with mitosis.
 Hydroxycarbamide (hydroxyurea ): inhibits ribonucleotide reductase.
 Mitoxantrone (mitozantrone): causes DNA chain breakage.
 Trilostane: inhibits adrenocortical steroid synthesis.
 Monoclonal antibodies: rituximab, alemtuzumab, Trastuzumab
 Imatinib: inhibits tyrosine kinase signalling pathways
Synthesis of Cyclophosphamide

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Structure-Activity Relationship of alkylating agent(Nitrogen mustards):
1.The biological activity of nitrogen mustards is based upon the presence of the bis-(2-
chloroethyl) grouping.
2. Bifunctional alkylating agents have greater activity than monofuctional alkylating agents,
e.g.Cyclophosphamide .
3. R=P-Butyric acid produces chlorambucil which is slowest acting & least toxic.
4. R=CH3 Produces a compound with cytotoxic activities but higher toxicities,e.g.
Mechlorehtamine
5. linkage of the bis-(2- chloroethyl) group to
election-rich substitutions such as unsaturated ring systems has yielded more stable drugs
with greater selective killing of tumor cells.
6. Substitution of one of the two chloroethyl groups on the cyclic phosphoamide nitrogen of
the oxazaphosphorine ring produces a compound with slower metabolism rate,requiring high
dose with higher toxicities, e.g. Ifosfamide.
Pharmacokinetics of
Cyclophosphamide

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ф Routes: Oral, intravenous
ф Bioavailability: >75% (oral)
ф Protein binding: >60%
ф Metabolism: Hepatic
ф Half life: 3-12 hours
ф Excretion: Renal
Indication of Cyclophosphamide
 Acute & chronic lymphocytic leukemias
 Hodgkin's diseases
 Multiple myeloma
 Neuroblastoma
 Breast, ovary, lung, & cervix cancer

Side-effects of Cyclophosphamide
 Nausea and vomiting
 Severe bone marrow depression
 Immunosuppression
 Alopecia
 Diarrhea
 Hemorrhagic cystitis
 Leukocytosis
 Amenorrhea
 Testicular atrophy
 Aspermia
 Sterility
 Neurotoxicity
 Blocks reproductive function and
 May produce menstrual irregularities or premature ovarian failure in women and
oligospermia in men.
Contraindication of Cyclophosphamide
-Bladder hemorrhage
-Leucopenia
-Thrombocytopenia
-Pregnancy

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Dose of Cyclophosphamide
Initial, adult dose of 40-50 mg per kg, given intravenously in divided doses over 2 to 5 days ;
Children : 2-8 mg per kg daily iv injection.
Available Market Preparation
Cyclophosphamide
 ENDOXAN Inj.
-Cycloph0sphamide anhydrous BP 200mg & 500mg as white powder in vial for
reconstitution: injection.
 ENDOXAN Tab.
-Cyclophosphamide BP 50 mg/tablet.