Cyclophosphamide
[CAS# 50-18-0]

Identification

• Classification: Biochemical >> Inhibitor >> Immune inhibitor
• Name: Cyclophosphamide
• Synonyms: 1-(Bis(2-chloroethyl)amino)-1-oxo-2-aza-5-oxaphosphoridine; 2-(Di(2-chloroethyl)amino)-1-oxa-3-aza-2-phosphacyclohexane 2-oxide
• Molecular Formula: C₇H₁₅Cl₂N₂O₂P
• Molecular Weight: 261.09
• CAS Registry Number: 50-18-0
• EC Number: 200-015-4
• SMILES: C1CNP(=O)(OC1)N(CCCl)CCCl

Properties

• Solubility: 43 mg/mL (water), 52 mg/mL (DMSO), 52 mg/mL (ethanol) (Expl.)
• Density: 1.3±0.1 g/cm³, Calc.^*
• Melting point: 41-45 ºC (Excp.)
• Index of Refraction: 1.506, Calc.^*
• Boiling Point: 336.1±52.0 ºC (760 mmHg), Calc.^*
• Flash Point: 157.1±30.7 ºC, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS05;GHS06;GHS07;GHS08 Dander
• Hazard Statements: H301-H302-H318-H340-H350-H360-H372
• Precautionary Statements: P203-P260-P264-P264+P265-P270-P280-P301+P316-P301+P317-P305+P354+P338-P317-P318-P319-P321-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Carcinogenicity	Carc.	1B	H350
Germ cell mutagenicity	Muta.	1B	H340
Acute toxicity	Acute Tox.	3	H301
Reproductive toxicity	Repr.	1A	H360
Reproductive toxicity	Repr.	1B	H360
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Serious eye damage	Eye Dam.	1	H318
Acute toxicity	Acute Tox.	4	H302
Carcinogenicity	Carc.	1A	H350
Germ cell mutagenicity	Muta.	1A	H340
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2	H319
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Germ cell mutagenicity	Muta.	2	H341
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	3	H331
Acute toxicity	Acute Tox.	3	H311

• Transport Information: UN 1851

Discovory and Applicatios

Cyclophosphamide is a widely used chemotherapy drug that belongs to the class of alkylating agents. It is primarily employed in the treatment of various types of cancer, including lymphomas, leukemia, breast cancer, and ovarian cancer, as well as in the treatment of autoimmune diseases such as rheumatoid arthritis and lupus. The compound was first synthesized in the 1950s as part of a broader effort to develop more effective chemotherapy agents. Its discovery and subsequent clinical application marked a significant advancement in the treatment of cancer and certain immune disorders.

The synthesis of cyclophosphamide can be traced back to the early 1950s when researchers were seeking to develop new drugs that could selectively target rapidly dividing cancer cells. It was discovered by researchers at the pharmaceutical company Merck, who were working to expand the range of available alkylating agents. Cyclophosphamide, originally named NSC-26271, was found to exhibit strong antitumor activity, leading to its testing in clinical trials.

Cyclophosphamide is a prodrug, meaning that it is metabolized in the body into its active form, phosphoramide mustard. The active form is a highly reactive molecule that interferes with DNA replication by forming covalent bonds with the DNA strands, resulting in crosslinking of the strands. This crosslinking prevents DNA from uncoiling and replicating, thus inhibiting cell division and inducing cell death. This mechanism is particularly effective against rapidly proliferating cells, which is why cyclophosphamide is especially useful in treating cancers. The drug is also effective in targeting immune cells, making it useful for treating autoimmune diseases.

Cyclophosphamide’s primary application is in cancer chemotherapy. It is commonly used in combination with other drugs in regimens designed to treat a variety of cancers, such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute leukemia, and breast cancer. Cyclophosphamide is often administered intravenously, though it can also be given orally in some cases. In the treatment of lymphomas and leukemia, cyclophosphamide is a key component of combination chemotherapy protocols that have significantly improved patient survival rates.

Beyond its oncological applications, cyclophosphamide is also used in the treatment of autoimmune diseases. It is particularly useful in diseases such as lupus nephritis and rheumatoid arthritis, where it suppresses the immune system to reduce inflammation and prevent further damage to tissues. The drug's immunosuppressive effects are achieved through its ability to deplete certain white blood cells that are involved in the inflammatory process.

Despite its effectiveness, cyclophosphamide is associated with a number of side effects, particularly due to its cytotoxic effects on both cancerous and healthy cells. These side effects include nausea, vomiting, hair loss, and bone marrow suppression, which can lead to a reduced ability to produce blood cells and an increased risk of infection. Other long-term side effects include an increased risk of secondary cancers, such as leukemia, due to the drug’s DNA-damaging effects. Additionally, cyclophosphamide can cause bladder toxicity, which can result in hemorrhagic cystitis. To mitigate these side effects, the drug is often administered with protective agents, such as mesna, which helps prevent bladder damage.

Research continues to investigate ways to reduce the side effects of cyclophosphamide while maintaining its therapeutic efficacy. Newer formulations and delivery methods are being explored to better target the drug to cancer cells and minimize damage to healthy tissues. Additionally, combination therapies involving cyclophosphamide and other novel agents are being tested to improve treatment outcomes and reduce the likelihood of drug resistance.

In conclusion, cyclophosphamide is a key chemotherapy drug with a wide range of applications in cancer treatment and the management of autoimmune diseases. Its discovery in the mid-20th century marked an important step forward in the fight against cancer, and its continued use in clinical practice demonstrates its effectiveness in targeting rapidly dividing cells. While its side effects are significant, ongoing research efforts aim to improve its safety profile and expand its therapeutic potential.