Semustine

From discovery to approval

1. 1972 · Earliest report found

   Semustine (methyl-CCNU, NSC-95441) is named 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, which differs from CCNU's cyclohexyl ring by one methyl group. The earliest paper found is a 1972 study in metastatic Lewis lung carcinoma (title only); clinical papers followed in 1973. Its synthesis was not traced.^{[2][3][4][5][6]}

2. No approval is recorded on this site.

How it works

A chloroethylating nitrosourea: this group alkylates DNA, first forming single-base adducts and then interstrand crosslinks that block replication and transcription. No semustine-specific mechanism study was read.^[1]

Where it came from and why

The sources read do not say why semustine was made. A 1976 review lists meCCNU with BCNU and CCNU as the best-known nitrosoureas and reports non-cross-resistance with other alkylating agents in mouse tumours.

Cancers

• Lung cancer

  A 1973 study of methyl-CCNU in lung cancer is titled as such; only the title was read.^[4]

• Gastrointestinal cancer (adjuvant)

  Semustine was given as adjuvant therapy in randomised trials in gastrointestinal cancer, pooled in a 1983 analysis of 3633 patients.^[7]

• Diffuse large B-cell lymphoma (transplant conditioning)

  A cohort study in China compared a conditioning regimen of oral semustine, etoposide, cytarabine and cyclophosphamide (CEAC), which its authors developed, with BEAM before autologous stem cell transplantation in 110 patients with diffuse large B-cell lymphoma.^[8]

Worth knowing

• In a pooled analysis of nine randomised trials in gastrointestinal cancer, leukaemic disorders developed in 14 of 2067 patients given semustine and in 1 of 1566 given other therapies (relative risk 12.4; 95% CI 1.7 to 250).^[7]
• The same 1983 analysis reported a six-year cumulative risk of a leukaemic disorder of 4.0 +/- 2.2% after semustine and concluded that nitrosoureas are leukaemogenic in humans.^[7]
• In the 2024 propensity-score-matched comparison of 22 patients given BEAM and 88 given CEAC, 5-year progression-free survival was 80% and 70% (P = 0.637) and 5-year overall survival 95% and 91% (P = 0.496).^[8]

References

1. Nikolova T, Roos WP, Krämer OH, Strik HM, Kaina B. Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling. Biochim Biophys Acta Rev Cancer. 2017;1868(1):29-39. PubMedDOI
2. Mayo JG, Laster WR Jr, Andrews CM, Schabel FM Jr. Success and failure in the treatment of solid tumors. 3. "Cure" of metastatic Lewis lung carcinoma with methyl-CCNU (NSC-95442) and surgery-chemotherapy. Cancer Chemother Rep. 1972;56(2):183-95. PubMed
3. Young RC, Walker MD, Canellos GP, Schein PS, Chabner BA, DeVita VT. Initial clinical trials with methyl-CCNU 1-(2-chlorethyl)-3-(4-methyl cyclohexyl)-1-nitrosourea (MeCCNU). Cancer. 1973;31(5):1164-9. PubMedDOI
4. Richards F 2nd, Pajak TF, Cooper MR, Spurr CL. Study of methyl-CCNU(NSC-95441) in the treatment of lung cancer. Cancer Chemother Rep. 1973;57(4):419-22. PubMed
5. Wasserman TH, Slavik M, Carter SK. Methyl-CCNU inclinical cancer therapy. Cancer Treat Rev. 1974;1(4):251-69. PubMedDOI
6. Schabel FM Jr. Nitrosoureas: a review of experimental antitumor activity. Cancer Treat Rep. 1976;60(6):665-98. PubMed
7. Boice JD Jr, Greene MH, Killen JY Jr, Ellenberg SS, Keehn RJ, McFadden E, et al. Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU). N Engl J Med. 1983;309(18):1079-84. PubMedDOI
8. Wang T, Liu P, Xu L, Gao L, Ni X, Tang G, et al. CEAC (oral semustine, etoposide, cytarabine and cyclophosphamide) vs BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen of autologous stem cell transplantation for diffuse large B-cell lymphoma: a post-hoc, propensity score-matched, cohort study in Chinese patients. Ann Hematol. 2024;103(2):575-582. PubMedDOI