Cyclophosphamide is a synthetic alkylating agent chemically related to the nitrogen mustards with antineoplastic and immunosuppressive activities. In the liver, cyclophosphamide is converted to the active metabolites aldophosphamide and phosphoramide mustard, which bind to DNA, thereby inhibiting DNA replication and initiating cell death.
Cyclophosphamide is an alkylating agent used in the treatment of several forms of cancer including leukemias, lymphomas, and breast cancer. Cyclophosphamide therapy is associated with minor transient serum enzyme elevations and has been linked to rare cases of acute liver injury. In addition, when given in high doses as a part of a myeloablative therapy, cyclophosphamide can cause acute sinusoidal obstruction syndrome.
Mechanism of Action
Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
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The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, & imidazole groups. The chemotherapeutic & cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents & may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine & pyrimidine bases of DNA- particularly, the 1 & 3 nitrogens of adenine, the 3 nitrogen of cytosine, & the 6 oxygen of guanine- also may be alkylated, as will be the phosphate atoms of the DNA chains & amino & sulfhydryl groups of proteins. /Alkylating agents/
Indications of Cyclophosphamide
Cyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients.
Therapeutic Uses of Cyclophosphamide
- Alkylating Agents; Antineoplastic Agents, Alkylating; Antirheumatic Agents; Carcinogens; Immunosuppressive Agents; Mutagens; Teratogens.
- The clinical spectrum of activity for cyclophosphamide is very broad. It is an essential component of many effective drug combinations for non-Hodgkin’s lymphomas. Complete remissions & presumed cures have been reported when cyclophosphamide was given as a single agent for Burkitt’s lymphoma. It is frequently used in combination with methotrexate (or doxorubicin) & fluorouracil as adjuvant therapy after surgery for carcinoma of the breast. Notable advantages of this drug are the availability of the oral route of admin & the possibility of giving fractionated doses over prolonged periods.
- For these reasons, it possesses a versatility of action that allows an intermediate range of use, between that of the highly reactive iv mechlorethamine & that of oral chlorambucil. Beneficial results have been obtained in multiple myeloma; chronic lymphocytic leukemia; carcinomas of the lung, breast, cervix, & ovary; & neuroblastoma, retinoblastoma, & other neoplasms of childhood. Because of its potent immunosuppressive properties, cyclophosphamide has received considerable attention for the control of organ rejection after transplantation & in nonneoplastic disorders associated with altered immune reactivity, including Wegener’s granulomatosis, rheumatoid arthritis, & the nephrotic syndrome in children.
- Furosemide may improve, renal blood flow, decrease resorption of sodium and chloride, and increase free water excretion. The initial dose of furosemide is 2 mg/kg, IV. This dosage can be doubled or tripled if urine output does not increase within 1 hr. However, if there is no response to 6 mg/kg, another approach should be tried. If effective, furosemide can be given parenterally at 2 mg/kg, bid., to maintain a diuresis.
- Consequently a higher survival rate was obtained in the following experimental groups; (cyclophosphamide 200 mg/kg, days 0 & 1) + bone marrow transplantation > (cyclophosphamide 400 mg/kg, day 0) + bone marrow transplantation, (nimustine hydrochloride 20 mg/kg, days 0 & 1) + bone marrow transplantation > (nimustine hydrochloride 40 mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide 200 mg/kg + nimustine hydrochloride 20 mg/kg, day 0) + bone marrow transplantation > (cyclophosphamide 400 mg/kg or nimustine hydrochloride 40 mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide 200 mg/kg, day 0) + (nimustine hydrochloride 20/kg, day 1) + bone marrow transplantation > (nimustine hydrochloride 20 mg/kg, day 0) + (cyclophosphamide 200 mg/kg, day 1) + bone marrow transplantation.
- Cyclophosphamide is indicated for the treatment of acute lymphoblastic (stem-cell) leukemia in children (including during remission to prolong the duration), and for treatment of acute myelogenous and acute monocytic leukemia.
- Cyclophosphamide is indicated for the treatment of chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis) and chronic lymphocytic leukemia.
- Cyclophosphamide is indicated for the treatment of adenocarcinoma of the ovary, breast carcinoma, neuroblastoma (in patients with disseminated disease.
- Cyclophosphamide is indicated for the treatment of/ small cell and non-small cell lung carcinoma, cervical carcinoma, and for endometrial carcinoma, bladder carcinoma, prostatic carcinoma, testicular carcinoma, and Wilms’ tumor and adrenocortical carcinoma .
- Cyclophosphamide is indicated for the treatment of Stage III and IV (Ann Arbor or Peter’s Staging System) Hodgkin’s disease and non-Hodgkin’s lymphomas including nodular or diffuse lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma, (and lymphoblastic lymphosarcoma
- Cyclophosphamide is indicated for the treatment of multiple myeloma.
- Cyclophosphamide is indicated for the treatment of advanced mycosis fungoides.
- Cyclophosphamide has indicated as an immunosuppressant in the treatment of steroid-resistant or frequently relapsing steroid-sensitive biopsy proven minimal-change nephrotic syndrome in children (and adults /NOT included in US product labeling/).
- Cyclophosphamide is indicated for the treatment of various sarcomas, including Ewing’s sarcoma, osteosarcoma, and soft tissue sarcomas.
- Cyclophosphamide is indicated for the treatment of Waldenstrom’s macroglobulinemia.
- Cyclophosphamide is indicated as first-line therapy, as a single agent or in combination with other chemotherapeutic agents, for treatment of Histiocytosis X (Letterer-Siwe disease).
- Cyclophosphamide is indicated for the treatment of thymoma.
- Cyclophosphamide is used for the treatment of germ cell ovarian, primary brain, and gestational trophoblastic tumors.
- Cyclophosphamide is used for its immunosuppressant activity, for prevention of rejection in homotransplantation.
- Cyclophosphamide is used as an immunosuppressant in the treatment of rheumatoid arthritis and other autoimmune diseases such as polymyositis (systemic dermatomyositis), multiple sclerosis, Wegener’s granulomatosis, systemic lupus erythematosus, and other types of vasculitis.
- Cyclophosphamide is used as an antitumor agent and experimentally for removal of fleece in adult sheep. The likelihood that cyclophosphamide residues will occur or pose a problem is remote.
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References
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