Semustine (MeCCNU, DB13647): A Comprehensive Pharmacological and Clinical Review

1. Introduction and Overview

1.1. Identification and Nomenclature

Semustine, an investigational antineoplastic agent, is widely recognized by its common abbreviation MeCCNU, which stands for Methyl-CCNU.[1] Its formal DrugBank accession number is DB13647.[3] The primary Chemical Abstracts Service (CAS) Registry Number assigned to Semustine is 13909-09-6.[3] Other CAS numbers, such as 33073-59-5 and 33185-87-4, have also been associated with the substance, potentially referring to different salt forms or isomers, though Semustine itself is typically handled as the free base.[3] It is classified pharmacologically as a small molecule drug [User Query]. Throughout its research and development, Semustine has been identified by various synonyms and codes, including Methyl-CCNU, Me-CCNU, and the National Cancer Institute (NCI) designation NSC 95441.[3]

1.2. Drug Class and Chemical Family

Semustine is a member of the nitrosourea class of alkylating agents.[1] This chemical family is characterized by its potent cytotoxic properties, primarily mediated through the alkylation of DNA, and a notable physicochemical property that allows many of its members, including Semustine, to penetrate the blood-brain barrier.[1] Chemically, Semustine is an organochlorine compound and is specifically categorized as an N-nitrosourea.[1] Its structure reveals it to be a 4-methyl derivative of lomustine (CCNU) and a methylated derivative of carmustine (BCNU), two other well-known nitrosourea anticancer drugs.[1]

1.3. Historical Context and Development

The development of Semustine occurred during the latter half of the 20th century, a period marked by intensive research into novel chemotherapeutic agents.[1] It emerged from systematic synthetic efforts focused on N-nitrosourea compounds, aiming to identify agents with improved efficacy or broader applicability in cancer treatment.[1] Its investigation was significantly advanced through programs supported by governmental research bodies like the NCI in the United States, as evidenced by its NSC identifier.[3] While a single, distinct pharmaceutical company developer is not consistently highlighted in the provided historical data, its origins are rooted in broader academic and governmental cancer research initiatives. Currently, Semustine is not an approved therapeutic agent; however, it remains available from specialized chemical suppliers such as MedKoo Biosciences and Sigma-Aldrich, strictly for research and investigational purposes.[9] Taj Pharma is also noted as a generic manufacturer, likely catering to the research chemical market given Semustine's regulatory status.[11]

1.4. Initial Therapeutic Rationale and Investigational Scope

The primary rationale for investigating Semustine as an anticancer drug was its potent antineoplastic activity, which is characteristic of DNA alkylating agents.[1] These agents induce cytotoxicity by forming covalent adducts with DNA, thereby disrupting its structure and function, and ultimately inhibiting cell replication and survival.[1]

A particularly compelling feature that drove Semustine's investigational scope was its lipophilic nature. This physicochemical property allows the molecule to readily cross biological membranes, most notably the blood-brain barrier (BBB).[1] The ability to achieve therapeutic concentrations within the central nervous system (CNS) made Semustine an attractive candidate for the chemotherapy of brain tumors, which are often shielded from many systemic anticancer drugs by the BBB.[1] Consequently, Semustine was evaluated in a diverse range of human cancers. These included primary and metastatic brain tumors (such as various gliomas, glioblastomas, and astrocytomas), several hematologic malignancies (including Hodgkin's disease and other lymphomas), gastrointestinal cancers (notably colorectal and gastric cancers), as well as other solid tumors like Lewis lung tumors and malignant melanoma.[1]

The lipophilicity of nitrosoureas like Semustine, which facilitates BBB penetration, represented a significant pharmacological advantage and was a key driver for their extensive investigation in the context of brain malignancies. However, this desirable pharmacokinetic attribute did not, in the case of Semustine, culminate in a therapeutic index (the balance between efficacy and toxicity) sufficiently favorable to secure clinical approval. The ability to reach CNS tumors was a necessary but not sufficient condition for success. The clinical utility of Semustine was ultimately undermined by a combination of modest efficacy in many settings and substantial systemic toxicities, including a significant long-term risk of carcinogenicity.[1] This underscores a persistent challenge in neuro-oncology: drugs must not only cross the BBB but also exhibit potent, selective anti-tumor activity at tolerable systemic doses.

2. Chemical Profile

2.1. Structure and Chemical Nomenclature

The formal International Union of Pure and Applied Chemistry (IUPAC) name for Semustine is 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea.[3] Its molecular formula is C10​H18​ClN3​O2​.[6] Structurally, Semustine is an organochlorine compound featuring a urea core. Key substitutions on this urea moiety define its chemical identity and pharmacological activity: one nitrogen atom of the urea is substituted with both a nitroso (-N=O) group and a 2-chloroethyl (-CH2CH2Cl) group, while the other nitrogen atom is substituted with a 4-methylcyclohexyl group. This specific arrangement places Semustine within the N-nitrosourea class of compounds. It is also recognized as the 4-methyl analog of lomustine (CCNU).[1]

2.2. Key Physicochemical Properties

Semustine possesses distinct physicochemical properties that influence its formulation, stability, and biological behavior:

• Molecular Weight: The calculated molecular weight of Semustine is approximately 247.72 g/mol.[5]
• Physical Description: In its solid state, Semustine typically appears as a light yellow powder or as crystalline material.[3]
• Solubility: Semustine exhibits very limited solubility in aqueous media, with a reported water solubility of 0.09 mg/mL.[3] It is, however, soluble in various organic solvents, including dimethyl sulfoxide (DMSO) at 250 mg/mL, absolute ethanol at 100 mg/mL, and is highly soluble in chloroform at 667 mg/mL.[3]
• Melting Point: The melting point of Semustine is approximately 64 °C, at which temperature it also undergoes decomposition.[3]
• Lipophilicity (LogP): The octanol-water partition coefficient (log Kow) for Semustine is 3.30.[3] This value indicates a significant degree of lipophilicity (fat-solubility), which is consistent with its ability to readily permeate biological membranes, including the BBB.
• Stability: In its solid form, Semustine is relatively stable under normal conditions but is sensitive to moisture and should be protected accordingly.[3] In solution, its stability is compromised. For example, a solution in 10% ethanol showed 2% decomposition after 6 hours when stored under refrigeration, but this increased to 25% decomposition at room temperature over the same period. Solutions prepared in methanol were also found to be unstable.[3] Thermal decomposition can lead to the emission of toxic fumes, including chlorine and nitrogen oxides.[3]

The pronounced lipophilicity and poor aqueous solubility of Semustine, along with its inherent instability in solution, were defining chemical characteristics. These factors heavily influenced its pharmaceutical development, favoring an oral solid dosage form for clinical trials. Furthermore, these properties significantly shaped its pharmacokinetic profile, particularly its capacity for CNS penetration and its susceptibility to rapid systemic metabolism. The high lipophilicity is a primary factor enabling passive diffusion across the BBB, aligning with its intended application for brain tumors.[1] Conversely, poor water solubility makes intravenous formulations difficult without specialized excipients, thus reinforcing the choice of oral administration.[1] The instability in aqueous and alcoholic solutions would also complicate liquid formulations and demand meticulous storage and handling protocols for the bulk drug and any extemporaneous preparations, potentially introducing variability if not strictly controlled.[3] Lipophilic compounds are often substrates for hepatic metabolic pathways, such as those mediated by CYP450 enzymes, which is consistent with the described metabolism of Semustine.[1] Thus, the drug's fundamental chemical nature directly influenced its pharmaceutical formulation, its key pharmacokinetic advantage (BBB permeability), and aspects of its metabolic fate, while also presenting challenges related to stability and consistent drug delivery.

2.3. Synthesis Overview

The synthesis of Semustine is rooted in the broader chemical exploration and development of N-Nitrosourea compounds, which were recognized for their anticancer potential.1

One documented synthetic pathway begins with the reaction of phosgene with aziridine, yielding the intermediate di(aziridin-1-yl)methanone. This intermediate, upon reaction with hydrochloric acid (HCl) generated in situ or added, undergoes ring-opening of the aziridine moieties to form 1,3-bis(2-chloroethyl)-urea. This urea derivative is then nitrosated, typically using sodium nitrite in an acidic medium such as formic acid, to introduce the nitroso group, yielding carmustine (BCNU). Carmustine is subsequently subjected to a controlled decomposition reaction in the presence of an excess (e.g., two equivalents) of 4-methylcyclohexylamine. This step results in the displacement of one of the chloroethylnitrosourea groups by the 4-methylcyclohexylamino moiety, forming 1-(2-chloroethyl)-3-(4-methylcyclohexyl)urea. The final step involves a second nitrosation reaction under similar conditions to introduce the nitroso group onto the remaining suitable nitrogen atom, thereby yielding Semustine (MeCCNU).1

An alternative synthetic approach has also been described, which utilizes 1-chloro-2-isocyanatoethane as a key starting material. This is reacted with 4-methylcyclohexylamine, often in the presence of a base catalyst like triethylamine (TEA), to form the urea precursor. This precursor is then nitrosated, using reagents such as sodium nitrite or tert-butyl nitrite, to produce Semustine.1

2.4. Available Forms for Investigation/Administration

For its investigational use in clinical trials and research, Semustine was typically supplied and handled as the pure, free base compound rather than as a salt form.[1] For patient administration during clinical studies, Semustine was most commonly formulated into oral pills. These pills were available in various strengths, reportedly ranging from 3.0 mg to 100 mg of the active pharmaceutical ingredient per unit.[1]

3. Pharmacology

3.1. Mechanism of Action

Semustine exerts its antineoplastic effects through a multi-faceted mechanism primarily centered on its properties as a DNA alkylating agent and its ability to interfere with DNA repair processes.

3.1.1. Alkylating Agent Activity

The principal mechanism by which Semustine induces cytotoxicity is through the alkylation of DNA.1 Semustine itself is a prodrug and requires metabolic activation to become pharmacologically active. This bioactivation occurs primarily in the liver and is mediated by the cytochrome P450 (CYP) mono-oxygenase enzyme system.1

The metabolic conversion of Semustine generates highly reactive electrophilic intermediates, most notably chloroethyl carbonium ions.1 These electrophiles are capable of attacking nucleophilic centers within the DNA molecule. The primary targets for alkylation are the N7 position of guanine and the O6 position of adenine residues in the DNA strands.1

The formation of these covalent adducts with DNA bases can lead to several critical types of DNA damage, including the formation of DNA interstrand cross-links (ICLs) and DNA-DNA cross-links.1 These cross-links physically tether the two strands of the DNA double helix or link different DNA segments, preventing their necessary separation during crucial cellular processes like DNA replication and transcription. Semustine can also induce depurination (loss of purine bases) and base-pair miscoding, further compromising DNA integrity.7

The consequence of this extensive DNA damage is a profound interference with DNA replication and transcription, leading to cell cycle arrest and the induction of apoptosis (programmed cell death). This cytotoxic effect is particularly pronounced in rapidly proliferating cells, such as cancer cells, which have a high demand for DNA synthesis.1 The electrophilic nature and reactivity of Semustine's alkylating species are reportedly enhanced under acidic conditions, which may influence its activity within certain tumor microenvironments.1

3.1.2. Role of Isocyanates and Protein Carbamoylation

In addition to the formation of chloroethylating species, the metabolic breakdown of Semustine also yields isocyanate moieties.8 These isocyanates are also reactive electrophiles and possess the ability to covalently modify cellular proteins through a process known as carbamoylation, where they react with nucleophilic groups on amino acid residues (e.g., lysine).8

A significant consequence of this protein carbamoylation is the potential inhibition of various critical cellular enzymes. Among the proteins susceptible to carbamoylation are enzymes involved in DNA repair pathways.8 Lomustine, a structurally similar nitrosourea, is also known to inhibit key enzymatic processes via carbamoylation.23

By impairing the function of DNA repair enzymes, the isocyanate-mediated carbamoylation can potentiate the cytotoxicity of the DNA alkylation caused by the chloroethylating species. If the cell's capacity to repair the Semustine-induced DNA lesions is compromised, the damage becomes more persistent and lethal, leading to a more effective induction of cell cycle arrest and apoptosis.8

The cytotoxic efficacy of Semustine is therefore derived from a dual mechanism: direct damage to DNA through alkylation and the formation of cross-links, and an indirect enhancement of this damage by inhibiting DNA repair processes through protein carbamoylation by its isocyanate metabolites. This two-pronged assault likely accounts for the significant potency of nitrosoureas. However, this same dual mechanism also contributes to their broad toxicity. The inhibition of DNA repair is a double-edged sword; while it enhances the anti-tumor effect, it also increases the likelihood of damage to normal, healthy cells. If DNA repair mechanisms in normal cells are also compromised alongside alkylation damage, the risk of mutations, chromosomal aberrations, and subsequent malignant transformation is heightened. This provides a mechanistic basis for understanding not only the acute toxicities of Semustine, such as myelosuppression, but also its recognized long-term carcinogenic risk.

3.1.3. Cell Cycle Specificity

Nitrosoureas, including Semustine, are generally classified as cell-cycle phase non-specific alkylating agents.[2] This implies that they can exert their DNA-damaging effects on cells regardless of the specific phase of the cell cycle (G0, G1, S, G2, or M). However, cells that are actively undergoing DNA replication (i.e., in the S-phase) may exhibit increased sensitivity due to the direct interference with the replication machinery and the reduced time available for DNA repair before cell division.

3.2. Pharmacokinetics

3.2.1. Absorption

Semustine was designed for oral administration, and studies indicate that it is well absorbed from the gastrointestinal tract following ingestion.[1]

3.2.2. Distribution

Owing to its high lipophilicity (log Kow = 3.30), Semustine exhibits rapid and extensive distribution into various body tissues after absorption.[1] A critical pharmacokinetic characteristic of Semustine is its ability to efficiently cross the blood-brain barrier (BBB). This results in significant penetration into the central nervous system (CNS), achieving potentially therapeutic concentrations in both brain tissue and cerebrospinal fluid (CSF).[1] This property was a major rationale for its investigation in the treatment of primary and metastatic brain tumors. While specific CSF-to-plasma concentration ratios for Semustine are not detailed in the provided materials, related CNS-active agents like temozolomide have shown CSF/plasma AUC ratios around 20% [24], and AZD1775 demonstrated unbound tumor-to-plasma ratios ranging from 1.3 to 24.4 in glioblastoma patients [25], offering a general context for the extent of CNS drug penetration achieved by some compounds. The plasma protein binding of Semustine is not explicitly stated, but its close analog, lomustine, is reported to be approximately 50% bound to plasma proteins [23]; a similar extent of binding might be anticipated for Semustine.

3.2.3. Metabolism

Semustine undergoes rapid and extensive biotransformation, primarily in the liver.[1] The cytochrome P450 (CYP) mono-oxygenase system plays a significant role in its metabolism.[1] Metabolic reactions include the hydroxylation of the cyclohexyl ring at various carbon positions and modifications to the 2-chloroethyl sidechain.[1] A crucial aspect of Semustine's metabolism is that many of the resulting metabolites retain alkylating activity and, therefore, contribute to the overall antineoplastic effect of the drug. These active metabolites are also reported to have prolonged plasma half-lives, leading to sustained systemic exposure to cytotoxic species.[1]

3.2.4. Excretion

The primary route of elimination for Semustine and its various metabolites is renal excretion. Studies have shown that up to 60% of an administered dose can be recovered in the urine in the form of metabolites within 48 hours of administration.[1] Minor amounts of the drug or its breakdown products may also be excreted via the fecal route or eliminated through the lungs as carbon dioxide, a byproduct of the molecule's degradation.[1]

3.2.5. Half-life

The parent drug, Semustine, is subject to rapid metabolism, resulting in a relatively short plasma half-life for the intact molecule.[1] However, its pharmacologically active metabolites are characterized by prolonged plasma half-lives.[1] This pharmacokinetic profile means that even after the parent drug is cleared, the body remains exposed to DNA-damaging species for an extended period. For comparison, the active metabolites of the related nitrosourea, lomustine, have reported elimination half-lives ranging from 16 to 48 hours.[23]

The pharmacokinetic characteristic of rapid metabolism into active metabolites with prolonged half-lives is a critical determinant of Semustine's overall pharmacological profile. This feature offers the potential for sustained anti-tumor activity from a single oral dose, as the body is continuously exposed to cytotoxic species. Such sustained exposure could be advantageous for targeting cancer cells that may cycle slowly or are only intermittently susceptible to DNA damage. However, this same pharmacokinetic property—prolonged exposure to active alkylating agents—concurrently increases the risk of cumulative and delayed toxicities to normal, healthy tissues. Tissues with high cell turnover rates, such as the bone marrow, and organs involved in drug metabolism and excretion, like the kidneys and liver, are particularly vulnerable. The observed cumulative dose-dependent nephrotoxicity [1] and the well-known myelosuppressive effects of nitrosoureas [2] are consistent with this prolonged exposure to active metabolites. The delayed onset of certain toxicities, such as nephrotoxicity which may only become apparent after more than a year of treatment [1], further supports the concept of damage accumulation resulting from these persistent active species. This pharmacokinetic profile underscores the inherent challenge in optimizing nitrosourea dosing regimens to maximize therapeutic efficacy while minimizing severe, long-term harm.

4. Investigational Clinical Applications and Efficacy

4.1. Spectrum of Investigated Cancers

Semustine was evaluated in clinical trials across a diverse range of human cancers, reflecting the broad cytotoxic activity often associated with alkylating agents and the specific interest in its CNS-penetrating capabilities.

• Brain Tumors: Given its lipophilicity and ability to cross the BBB, a primary focus of Semustine's investigation was on CNS malignancies. This included various types of gliomas, glioblastoma multiforme, astrocytomas, and metastatic brain tumors.[1]
• Hematologic Malignancies: Clinical studies explored its utility in Hodgkin's lymphoma and other non-Hodgkin's lymphomas.[1]
• Gastrointestinal Cancers: Semustine was trialed in patients with advanced colorectal cancer, as an adjuvant therapy for surgically resected rectal cancer, and for gastric cancer.[1]
• Lung Cancer: Investigations included its use against Lewis lung tumors (a common preclinical model) and epidermoid carcinoma of the lung in clinical settings.[1]
• Other Solid Tumors: Malignant melanoma was another solid tumor type in which Semustine's activity was assessed.[1]
• Leukemia: The L1210 leukemia model, a standard for preclinical anticancer drug screening in mice, is mentioned in the context of Semustine's activity.[1]
• Extranodal NK/T-cell Lymphoma (Nasal Type): A specific clinical trial evaluated Semustine in combination with the CEOP (cyclophosphamide, epirubicin, vincristine, prednisone) regimen for patients with this particular lymphoma subtype.[14]

4.2. Summary of Clinical Trial Evidence

Despite its broad investigation, a consistent theme emerging from the available clinical trial data is that Semustine often demonstrated limited efficacy and generally failed to establish a clear therapeutic advantage over existing treatments or comparators, particularly when its significant toxicity profile was considered.[1] The following table summarizes key findings from reported clinical trials:

Indication	Clinical Setting	Phase	Semustine-containing Regimen (Dose if available)	Comparator Regimen	Key Efficacy Outcomes (ORR, PFS, OS)	Conclusion Regarding Semustine's Role/Efficacy	Snippet ID(s)
Recurrent Glioblastoma or Anaplastic Astrocytoma	Recurrent	Not Specified (likely II/III)	MeCCNU (Semustine) 150 mg/m² orally, q28d	Temozolomide (TMZ)	PFS @ 6 months: MeCCNU 55.88% vs. TMZ 78.87% (p < 0.05). ORR: MeCCNU 21.27% (CR 6.38%, PR 14.89%) vs. TMZ 45.83% (CR 19.44%, PR 26.39%) (p < 0.01).	TMZ demonstrated superior efficacy and better safety profile.	17
Advanced Colorectal Cancer (post-5-FU)	Metastatic, Second-line	Randomized	MeCCNU + Vincristine (VCR)	MeCCNU + Dacarbazine (DTIC); MeCCNU + DTIC + VCR; MeCCNU + β-2'-deoxythioguanosine	PR rates: 6% (MeCCNU+VCR), 16% (MeCCNU+DTIC), 5% (MeCCNU+DTIC+VCR). Median Survival: 19 wks, 28 wks, 25 wks respectively. No statistically significant differences.	Low response rates, modest survival. No clear benefit of specific combinations.	20
Advanced Colorectal Cancer	Metastatic	Not Specified	5-FU + MeCCNU	Historical controls (untreated)	Only 2 PRs in 52 patients. Median survival 9 months.	Lack of effectiveness; comparable to untreated disease.	21
Rectal Adenocarcinoma	Adjuvant (post-resection)	Randomized	Radiation + 5-FU, then 5-FU + MeCCNU (12 mo)	Radiation + 5-FU, then escalating 5-FU (6 mo)	Recurrence: 54% vs. 43%. 3-yr DFS: 54% vs. 68%. 3-yr OS: 66% vs. 75%.	MeCCNU not an essential component; trends favored non-MeCCNU arm.	15
Extranodal NK/T-cell Lymphoma, Nasal Type (Stage IE/IIE)	Induction	Phase II, Randomized	CEOP + Semustine (CEOP-S)	CEOP alone	ORR: 62.2% (CEOP-S) vs. 57.9% (CEOP) (p=0.71). 2-yr OS: 62.2% (CEOP-S) vs. 73.3% (CEOP) (p=0.37).	Addition of Semustine did not improve efficacy.	14
Advanced Hodgkin's Disease	Advanced	Randomized	Methyl-CCNU (Semustine) 150 mg/m² q6w	CCNU (Lomustine) 100 mg/m² q6w	Response Rate: 15% (Semustine) vs. 42% (Lomustine) in HD.	CCNU (Lomustine) superior to Methyl-CCNU (Semustine) for Hodgkin's Disease.	18
Advanced Breast Cancer	Advanced	Phase II	Semustine (NSC 95441)	Single agent	Results not detailed in snippet.	Efficacy not ascertainable from snippet.	12

The collective evidence from these trials paints a picture of consistent underperformance for Semustine across a variety of oncological indications and clinical settings. Whether employed as a single agent or as part of combination chemotherapy regimens, and whether in the metastatic or adjuvant setting, Semustine rarely demonstrated a significant or clinically meaningful improvement in efficacy outcomes compared to control treatments or historical benchmarks. This lack of compelling therapeutic benefit, particularly when viewed in light of its substantial and serious toxicity profile (detailed in Section 5), created an insurmountable barrier to its further clinical development and regulatory approval. The data strongly suggest that while Semustine possessed the biochemical capacity to induce DNA damage, this did not reliably translate into superior patient outcomes in the clinical arena. This highlights a common challenge in oncology: a plausible mechanism of action does not always predict clinical success, especially if the therapeutic window is narrow.

5. Safety, Toxicity, and Risk Profile

5.1. Common and Serious Adverse Effects

The clinical use of Semustine was associated with a range of significant adverse effects, many of which are characteristic of the nitrosourea class of alkylating agents.

• Myelosuppression: This was a prominent and often dose-limiting toxicity. It typically manifested as leukopenia (a decrease in white blood cells, increasing infection risk) and thrombocytopenia (a decrease in platelets, increasing bleeding risk).[12] For instance, in clinical trials involving patients with advanced colorectal cancer, nadirs for white blood cell counts below 2,000/mm³ were observed in 7-12% of patients, and platelet count nadirs below 50,000/mm³ occurred in 9-19% of patients.[20] Similar to its analog lomustine, Semustine's myelosuppressive effects were likely delayed, dose-dependent, and cumulative, complicating patient management and requiring careful hematologic monitoring.[23]
• Gastrointestinal Toxicity: Nausea and vomiting were frequently reported and could be severe.[2] In one colorectal cancer study, severe vomiting was noted in up to 14% of participants.[20] Diarrhea was also a common gastrointestinal complaint.
• Nephrotoxicity: Kidney damage emerged as a serious cumulative toxicity associated with Semustine, particularly with prolonged administration and high total doses.[1] Severe renal damage, including observations of decreased kidney size, was reported in pediatric patients who received total cumulative doses exceeding 1.5 g/m².[1] An increased risk of renal abnormalities was generally observed in patients whose cumulative dose reached 1.4 g/m² or more, with approximately 25% of such patients being affected.[1] This nephrotoxicity often had a delayed onset, sometimes becoming apparent only after a year or more of treatment.[1] The pattern is consistent with the known renal toxicity of other nitrosoureas like lomustine.[23]
• Hepatotoxicity: While specific data for Semustine-induced hepatotoxicity are not extensively detailed in the provided snippets, its structural analog lomustine is associated with liver toxicity, including elevations in liver transaminases, alkaline phosphatase, and bilirubin.[23] Given Semustine's hepatic metabolism, a similar potential for hepatotoxicity is plausible and would necessitate liver function monitoring.
• Pulmonary Toxicity: Direct information on Semustine-induced pulmonary toxicity is limited in the snippets. However, lomustine is known to cause or exacerbate pulmonary infiltrates and fibrosis, typically after six months or more of treatment.[23] This raises the possibility of similar chronic lung toxicity with Semustine.
• Alopecia: Hair loss was a reported side effect.[2]
• Fatigue: A common constitutional symptom experienced by patients undergoing Semustine therapy.[2]

5.2. Carcinogenicity and Long-Term Risks

One of the most critical safety concerns associated with Semustine is its established carcinogenicity in humans.

• Classification as a Human Carcinogen: Semustine is classified as a Group 1 carcinogen ("carcinogenic to humans") by the International Agency for Research on Cancer (IARC).[9] The U.S. National Toxicology Program (NTP) also lists Semustine as a substance known to be a human carcinogen.[3]
• Induction of Secondary Malignancies: There is compelling evidence from clinical trials that treatment with Semustine is associated with an increased risk of developing secondary malignancies, particularly acute leukemia, as a delayed adverse effect.[1] This risk is also recognized for related nitrosoureas like lomustine.[23]
• A notable clinical trial involving 2067 patients treated with Semustine for gastrointestinal cancer documented 14 cases of acute leukemia that were attributed to the chemotherapy.[1]
• In this cohort, the estimated risk of developing a leukemia-related disorder within six years following Semustine treatment was approximately 4%.[1] This finding was particularly alarming because such secondary leukemias had not been a recognized complication in this patient population prior to the introduction of nitrosourea-based chemotherapy regimens.[1]

The established carcinogenicity of Semustine represents a significant paradox: a drug developed to treat cancer was itself found to cause cancer. This inherent risk, particularly the induction of often fatal secondary leukemias, created an unacceptable risk-benefit profile, especially when considering its generally modest efficacy in many of the investigated cancer types. The DNA alkylating mechanism of action, while responsible for its cytotoxic effects against tumor cells, also carries an intrinsic mutagenic potential. If this DNA damage occurs in normal hematopoietic stem cells or other progenitor cells and is not adequately repaired (a process potentially further compromised by the carbamoylating activity of Semustine's metabolites which can inhibit DNA repair enzymes), it can lead to the oncogenic mutations that drive leukemogenesis. This severe long-term toxicity was a primary factor in the decision to halt its clinical development for therapeutic use.

5.3. Drug Interactions

The available information on specific drug interactions with Semustine is limited, but some interactions can be documented or inferred based on its chemical class and metabolism.

Interacting Drug/Drug Class	Nature of Interaction (Pharmacokinetic/Pharmacodynamic)	Potential Clinical Consequence	Strength of Evidence/Source	Snippet ID(s)
Local Anesthetics (e.g., Chloroprocaine, Cinchocaine, Cocaine)	Pharmacodynamic	Increased risk or severity of methemoglobinemia	Direct Semustine data	27
Other Myelosuppressive Agents (e.g., other chemotherapy drugs, radiation therapy)	Pharmacodynamic (Additive Toxicity)	Exacerbation of bone marrow suppression (leukopenia, thrombocytopenia, anemia)	Inferred from class effect and general oncology principles	2
CYP450 Inducers (e.g., Phenytoin, Rifampin)	Pharmacokinetic (Increased Semustine metabolism)	Decreased plasma concentrations of Semustine and its active metabolites, potentially leading to reduced efficacy	Inferred from Semustine's metabolism and general pharmacology	1
CYP450 Inhibitors (e.g., certain azole antifungals, protease inhibitors)	Pharmacokinetic (Decreased Semustine metabolism)	Increased plasma concentrations of Semustine and its active metabolites, potentially leading to increased toxicity	Inferred from Semustine's metabolism and general pharmacology	1
Live Vaccines	Pharmacodynamic (Immunosuppression)	Increased risk of disseminated infection from the vaccine virus; diminished vaccine efficacy	Inferred from lomustine data and general principles of chemotherapy	28 (for lomustine)

This table highlights the importance of considering potential drug interactions. The risk of additive myelosuppression with other cytotoxic therapies is a standard concern in oncology. Given Semustine's hepatic metabolism via CYP450 enzymes, co-administration with strong inducers or inhibitors of these enzymes could significantly alter its exposure and, consequently, its efficacy and safety profile. While direct extensive interaction studies for Semustine are not detailed, the profile of its close analog, lomustine, which has numerous documented interactions [28], suggests a high likelihood of a similar interaction spectrum for Semustine.

5.4. Contraindications and Precautions

Based on its known toxicities and the properties of the nitrosourea class, the use of Semustine would be contraindicated or require significant precaution in several patient populations:

• Pre-existing Severe Myelosuppression: Patients with significantly compromised bone marrow function would be at high risk of life-threatening cytopenias.[2]
• Significant Hepatic or Renal Impairment: Given its hepatic metabolism and renal excretion of metabolites, pre-existing severe liver or kidney disease would likely alter its pharmacokinetics and exacerbate toxicity.[1]
• Hypersensitivity: A known history of allergic reactions to Semustine or other nitrosourea compounds would be a contraindication.[2]
• Pregnancy and Lactation: Semustine is presumed to be teratogenic and harmful to a nursing infant, making its use contraindicated during pregnancy and lactation. This is based on general principles for cytotoxic chemotherapy agents and data from related compounds like lomustine.[2]
• Elderly Patients: Increased caution would be necessary for geriatric patients, who may have reduced organ function and be more susceptible to the toxic effects of chemotherapy (inferred from lomustine guidance).[23]

6. Regulatory History and Current Status

6.1. Development and Investigational Use

Semustine was the subject of extensive clinical investigation as an antineoplastic agent, primarily during the 1970s and 1980s.[14] Its development was supported by research institutions, including the National Cancer Institute (NCI), which assigned it investigational codes such as NSC 95441.[3] Throughout this period, it was classified as an Investigational New Drug (IND).[3]

6.2. Regulatory Approval Status

Despite the considerable research efforts and numerous clinical trials conducted, Semustine never received marketing approval from major regulatory agencies like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any therapeutic indication.[1] General information regarding FDA and EMA regulatory processes [29] does not indicate any approval specific to Semustine. Its status in DrugBank is noted as "Not Annotated" under "Drug Description" in one contextual search [4], which may reflect its non-approved and largely historical standing. MedKoo explicitly states that Semustine "has been taken off the drug market for investigation of its cancerous effects" [9], implying that any investigational use programs were terminated due to overwhelming safety concerns.

6.3. Reasons for Discontinuation/Withdrawal from Widespread Development

The primary factors leading to the cessation of Semustine's clinical development and its failure to achieve regulatory approval were:

• Carcinogenicity: The most critical and decisive reason was the conclusive evidence establishing Semustine as a human carcinogen. The documented risk of inducing secondary malignancies, particularly acute leukemia, in patients treated with the drug rendered its risk-benefit profile unacceptable.[1]
• Unfavorable Risk-Benefit Profile: Beyond its carcinogenicity, Semustine exhibited a profile of significant acute and cumulative toxicities, including severe myelosuppression and nephrotoxicity. When weighed against its generally modest or non-superior clinical efficacy observed in most trials, the overall risk-benefit assessment was unfavorable.[13]

The development trajectory of Semustine and its ultimate failure to gain approval serve as a significant historical example of how evolving regulatory standards and an improved understanding of long-term drug toxicities impact pharmaceutical development. In an earlier era, a drug with Semustine's level of activity might have progressed further. However, as the scientific community and regulatory bodies gained a deeper appreciation for delayed adverse events like carcinogenicity, and as the methodologies for assessing safety and efficacy became more rigorous, the bar for approval became justifiably higher. The accumulation of evidence regarding Semustine's potential to cause secondary leukemias, coupled with its IARC Group 1 carcinogen classification [9], would be a near-insurmountable obstacle to approval by contemporary standards. This case likely contributed to the increased stringency in the safety evaluation of subsequent alkylating agents and other genotoxic therapies.

6.4. Current Status

Currently, Semustine is primarily a compound of historical and research interest. It is not used therapeutically.

• It is available from various chemical suppliers, such as Cayman Chemical [5], GLPBIO [6], MedKoo [9], and Sigma-Aldrich [10], but strictly for laboratory research purposes. This typically involves its use in in vitro studies, as a reference compound for toxicological assessments, or in mechanistic studies related to DNA alkylation and nitrosourea pharmacology.
• It continues to be referenced in scientific literature, predominantly in historical reviews of cancer chemotherapy, discussions on drug-induced carcinogenesis, or in comparative toxicological studies involving other alkylating agents.[17]

7. Conclusion

7.1. Recapitulation of Semustine's Pharmacological and Clinical Profile

Semustine (MeCCNU, DB13647) is a lipophilic, orally administered nitrosourea derivative that functions as a potent DNA alkylating agent. Its proposed mechanism of action involves metabolic activation to reactive electrophilic species that induce DNA interstrand cross-links and other DNA lesions, as well as carbamoylation of cellular proteins, including DNA repair enzymes. This dual action leads to the inhibition of DNA replication and transcription, ultimately resulting in cytotoxicity, particularly against rapidly proliferating cancer cells. Its ability to penetrate the blood-brain barrier made it an attractive investigational candidate for a variety of malignancies, most notably brain tumors, but also including lymphomas, gastrointestinal cancers, and melanoma.

7.2. Determinants of Developmental Failure

Despite a strong mechanistic rationale and favorable pharmacokinetic properties for CNS penetration, Semustine's journey through clinical development was ultimately unsuccessful. Several key factors contributed to this outcome:

• Limited Clinical Efficacy: Across numerous clinical trials and diverse cancer indications, Semustine generally failed to demonstrate compelling efficacy. It rarely showed superiority over existing standard treatments and, in some instances, performed worse than comparator regimens or offered only marginal, inconsistent activity.
• Significant Toxicity Profile: The therapeutic use of Semustine was associated with substantial acute and cumulative toxicities. Dose-limiting myelosuppression (leukopenia and thrombocytopenia) and delayed, cumulative nephrotoxicity were particularly problematic adverse effects that complicated its administration and limited its tolerability.
• Unacceptable Carcinogenic Risk: The most critical factor leading to the discontinuation of Semustine's development was the definitive evidence of its carcinogenicity in humans. Clinical studies documented an increased risk of secondary acute myeloid leukemia in patients who had received Semustine, a long-term adverse effect that rendered its overall risk-benefit profile untenable for therapeutic use.

7.3. Legacy and Current Relevance in Pharmacology and Oncology

Although Semustine did not achieve clinical utility as an approved anticancer drug, its history provides valuable lessons and maintains relevance in the fields of pharmacology and oncology.

• Case Study in Drug Development: Semustine serves as an important historical case study highlighting the complex interplay between a drug's mechanism of action, its pharmacokinetic properties, its efficacy, and its short- and long-term safety. It underscores the principle that even drugs with a strong preclinical rationale and desirable properties (like BBB penetration) can fail if they do not offer a clear and substantial clinical benefit that outweighs their risks.
• Understanding Nitrosourea Toxicology: The study of Semustine contributed significantly to the understanding of the toxicology of nitrosourea compounds, particularly regarding their potential for delayed nephrotoxicity and, most critically, their carcinogenicity. This knowledge has informed the development and use of other alkylating agents.
• Impact on Regulatory Standards: The experience with Semustine and similar agents likely contributed to the evolution of more stringent regulatory requirements for the safety evaluation of new anticancer drugs, with a greater emphasis on long-term follow-up to detect delayed toxicities such as secondary malignancies.
• Tool for Research: Today, Semustine is utilized as a research chemical, aiding in studies focused on DNA alkylation mechanisms, drug-induced carcinogenesis, the pharmacology of nitrosoureas, and the development of strategies to overcome drug resistance or mitigate chemotherapy-induced toxicities.

The story of Semustine is a compelling reminder of the central importance of the therapeutic index in drug development. The therapeutic index, which quantifies the balance between a drug's desired therapeutic effects and its adverse effects, was unacceptably narrow for Semustine. This was primarily due to its severe long-term toxicity, most notably its carcinogenicity, which overshadowed any modest or inconsistent clinical benefits observed. The fundamental medical principle of primum non nocere (first, do no harm) is particularly salient in oncology, where treatments themselves can carry substantial inherent risks. The administration of a therapy that carries a demonstrable risk of inducing a new, often fatal, malignancy, such as acute leukemia [1], directly contravenes this principle if the drug does not offer a life-saving advantage or fill a critical unmet need where no safer alternatives exist. Semustine's failure to show superior efficacy in most clinical settings meant that its carcinogenic risk could not be justified. This case reinforces the ethical imperative in pharmaceutical development to rigorously assess both immediate and, critically, long-term safety, and to weigh these risks meticulously against clearly demonstrated clinical benefits.

8. References

1 Wikipedia. Semustine.

3 PubChem. Compound Summary: Semustine.

5 Cayman Chemical. Product Information: Semustine.

6 GLPBIO. Product Information: Semustine.

2 Patsnap Synapse. Article: What is Semustine used for? (June 15, 2024).

8 Patsnap Synapse. Article: What is the mechanism of Semustine? (July 18, 2024).

1 DrugFuture.com. Martindale - The Complete Drug Reference: Semustine.

12 NCATS Inxight: Drugs. Semustine Overview.

29 Morningstar. News: FDA Accepts Resubmission of BLA for Narsoplimab... (May 06, 2025).

30 The Center for Biosimilars. Article: Biosimilar Approvals Streamlined... (Undated).

14 PubMed. Abstract: A randomized phase II study of CEOP with or without semustine... (Lin et al., 2009 Dec).

15 PubMed. Abstract: Radiation therapy and fluorouracil with or without semustine... (Gastrointestinal Tumor Study Group, 1992 Apr).

13 DrugFuture.com. Martindale - The Complete Drug Reference: Semustine (Pharmacokinetics & Nephrotoxicity sections).

23 Wikipedia. Lomustine.

27 DrugBank Online. Semustine Drug Interactions (Excerpt).

28 Drugs.com. Lomustine Interactions.

4 DrugBank Online. Category: Nitrosourea Compounds.

3 PubChem. Compound Summary: Semustine (Identifiers section).

22 NCI Dictionary of Cancer Terms. Definition: semustine.

7 NCI Drug Dictionary. Definition: semustine.

23 Wikipedia. Lomustine (Safety section).

31 U.S. Food & Drug Administration. Clinical Review(s) - Trazimera (Example BLA review, for context on regulatory process).

2 Patsnap Synapse. Article: What is Semustine used for? (June 15, 2024 - covering multiple aspects).

9 MedKoo Biosciences. Product Information: Semustine.

34 National Toxicology Program. Appendices A-G; 15th RoC 2021 (General information on carcinogen classification).

16 American Cancer Society. Known and Probable Human Carcinogens (Lists Semustine).

10 Sigma-Aldrich. Product Detail: Semustine.

9 MedKoo Biosciences. Product Information: Semustine (Theoretical Analysis section).

3 PubChem. Compound Summary: Semustine (Experimental Properties section).

20 PubMed. Abstract: Combination chemotherapy containing semustine (MeCCNU) in patients with advanced colorectal cancer... (Bruckner et al., 1983 Apr).

32 European Medicines Agency. Nitrosamine impurities (General regulatory context).

33 AgencyIQ by POLITICO. EMA finalizes clinical anticancer therapeutic guidance update (General regulatory context).

8 Patsnap Synapse. Article: What is the mechanism of Semustine? (July 18, 2024 - detailed mechanism).

1 Wikipedia. Semustine (Mechanism of action, Synthesis, Cancer types treated, Carcinogenicity sections).

17 EMBL-EBI ChEBI. Entry CHEBI:6863 for semustine (Includes abstract comparing TMZ to MeCCNU in gliomas).

18 PubMed. Abstract: Comparison of methyl-CCNU and CCNU in patients with advanced forms of Hodgkin's disease... (Lessner et al., 1975 Sep).

9 MedKoo Biosciences. Product Information: Semustine (General information).

11 Taj Oncology. Product Page: Semustine 10mg Capsules.

19 PubMed. Abstract: Prognostic value of extent of resection in MGMT-methylated glioblastoma... (Mentions CCNU/TMZ, not directly Semustine efficacy).

20 PubMed. Abstract: Combination chemotherapy containing semustine (MeCCNU) in patients with advanced colorectal cancer....20

21 PubMed. Abstract: Lack of effectiveness of combined 5- fluorouracil and methyl-CCNU therapy in advanced colorectal cancer. (Lokich et al., 1977 Dec).

26 PubMed Central. Adjuvant Chemotherapy for Stage II/III Colon Cancer: Results From the ACCENT Database. (Provides context on colon cancer adjuvant therapy).

25 PubMed Central. Article: A physiologically based pharmacokinetic model to predict human brain tumor penetration... (Provides context on CNS drug penetration modeling, mentions AZD1775).

24 PubMed. Abstract: Population pharmacokinetics of temozolomide in patients with malignant glioma... (Provides context on TMZ CNS penetration).

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