Irinotecan hydrochloride trihydrate
[CAS# 136572-09-3]

Identification

• Classification: Biochemical >> Natural biochemical product
• Name: Irinotecan hydrochloride trihydrate
• Synonyms: (S)-[1,4'-Bipiperidine]-1'-carboxylic acid 4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester hydrochloride trihydrate
• Molecular Formula: C₃₃H₃₈N₄O₆.HCl.3(H₂O)
• Molecular Weight: 677.19
• CAS Registry Number: 136572-09-3
• EC Number: 603-967-2
• SMILES: CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)

Properties

• Melting point: 250-256 °C (dec.)

Safety Data

• Hazard Symbols: GHS07;GHS08 Danger
• Risk Statements: H302-H341-H360
• Safety Statements: P203-P264-P270-P280-P301+P317-P318-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	4	H302
Reproductive toxicity	Repr.	1B	H360
Germ cell mutagenicity	Muta.	2	H341
Acute toxicity	Acute Tox.	4	H312
Skin irritation	Skin Irrit.	2	H315
Germ cell mutagenicity	Muta.	1B	H340
Acute toxicity	Acute Tox.	4	H332
Specific target organ toxicity - single exposure	STOT SE	3	H335
Carcinogenicity	Carc.	2	H351
Eye irritation	Eye Irrit.	2	H319

Discovery and Applications

Irinotecan hydrochloride trihydrate is a chemotherapy drug primarily used in the treatment of various cancers, including metastatic colorectal cancer, small-cell lung cancer, and gastric cancer. It is a water-soluble salt form of irinotecan, a topoisomerase I inhibitor that works by interfering with the DNA replication process in rapidly dividing cancer cells. This drug is often used in combination with other chemotherapeutic agents to enhance its effectiveness and reduce the potential for resistance.

The discovery of irinotecan hydrochloride trihydrate dates back to the late 1980s, when it was first developed by the Japanese pharmaceutical company, Daiichi Sankyo. The compound was initially synthesized as part of a research effort aimed at discovering novel cancer treatments by targeting the enzymes responsible for DNA replication. Irinotecan belongs to a class of compounds called camptothecin analogs, which are derived from the naturally occurring alkaloid camptothecin, first isolated from the plant *Camptotheca acuminata* in the 1950s. Camptothecin itself was found to have strong anticancer properties, but it was too toxic for clinical use, leading researchers to develop derivatives with improved safety profiles.

Irinotecan works by inhibiting topoisomerase I, an enzyme that is crucial for DNA replication and transcription. Topoisomerase I creates transient single-strand breaks in the DNA helix to relieve torsional strain that builds up during the unwinding of DNA. Irinotecan interferes with the enzyme's ability to reseal these breaks, leading to the accumulation of DNA damage and ultimately cell death, particularly in rapidly dividing cancer cells. The drug is particularly effective in the treatment of cancers that have a high rate of cell division, making it useful for colorectal, small-cell lung, and gastric cancers.

The compound is typically administered intravenously in a clinical setting, often as part of combination chemotherapy regimens. One of the most common regimens involves the combination of irinotecan with 5-fluorouracil and leucovorin, a strategy known as FOLFIRI, which has been widely used in the treatment of metastatic colorectal cancer. In this regimen, irinotecan acts synergistically with 5-fluorouracil, a thymidylate synthase inhibitor, to further impair cancer cell DNA synthesis and promote cell death.

Irinotecan hydrochloride trihydrate is administered through an infusion, and the dosing schedule depends on the specific cancer being treated as well as the patient's overall health and response to the drug. The treatment may involve repeated cycles with periods of rest in between, and the drug is typically given every two or three weeks. The duration and frequency of treatment depend on factors such as the type of cancer, the response to therapy, and any side effects experienced.

The most common side effects of irinotecan include diarrhea, neutropenia (low white blood cell count), nausea, vomiting, and hair loss. Diarrhea can be particularly problematic, and patients are often given medications to help manage this side effect. The drug can also cause more severe toxicities, such as febrile neutropenia, which may require dose adjustments or discontinuation of therapy. In addition, irinotecan is associated with delayed toxicity, which can manifest several days after administration and can result in severe diarrhea or hematologic toxicity.

Despite these side effects, irinotecan has been a critical component of chemotherapy regimens for several types of cancer. It is particularly valuable in metastatic colorectal cancer, where it has significantly improved survival rates when combined with other drugs like 5-fluorouracil. Ongoing research continues to explore ways to optimize its use, including strategies to minimize side effects and overcome resistance mechanisms. Newer formulations and targeted drug delivery systems are also being investigated to improve its clinical efficacy and reduce systemic toxicity.

Irinotecan hydrochloride trihydrate remains one of the cornerstone therapies in the management of advanced gastrointestinal and other cancers, offering a vital treatment option in the fight against malignancies with high mortality rates.

References

2000. 5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomised phase II study of the Southern Italy Oncology Group. Annals of Oncology, 11(8).
DOI: 10.1023/a:1008342928408

2003. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Molecular Cancer Therapeutics, 2(4).
URL: https://pubmed.ncbi.nlm.nih.gov/12700281

2024. EGFR-targeting polydopamine nanoparticles co-loaded with 5-fluorouracil, irinotecan, and leucovorin to potentially enhance metastatic colorectal cancer therapy. Scientific Reports, 14(1).
DOI: 10.1038/s41598-024-80879-0