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temozolomide (SI 053 / Temodex / SI053)

✓ Approved

Double Bond Pharmaceutical · Small Molecule · Small Molecule

What is temozolomide?

temozolomide is a small molecule developed by Double Bond Pharmaceutical. It is approved for therapeutic indications via intratumoral injection.

Drug Profile

Brand NamesSI 053, Temodex, SI053
CompanyDouble Bond Pharmaceutical
Drug ClassSmall Molecule
RouteIntratumoral Injection
StatusApproved
Sources: ClinicalTrials.gov, Double Bond Pharmaceutical

Therapeutic Indications

temozolomide is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Brain neoplasm malignant✓ Approved

Related Research Articles

PubMedAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026-08-29

Chemotherapy-Activated GSK3β-DNMT1 Signaling Upregulates CD47 to Evade Macrophage Phagocytosis and Drive Temozolomide Resistance in Glioblastoma.

Li Jie J, Ying Shuai S, Zhang Yi Y, Wang Jingjing J et al.

Temozolomide (TMZ) remains the first-line therapy for glioblastoma (GBM) patients. However, the mechanisms underlying the emergence of acquired TMZ resistance after treatment are unclear. Here, we reveal the critical role of macrophage phagocytosis in GBM recurrence and acquired TMZ resistance. Mechanistically, TMZ treatment sustained GSK3β activation and promoted its interaction with DNMT1. This led to the phosphorylation of DNMT1 at the previously unrecognized S977 site for its K981-dependent ubiquitination and destabilization. The downregulation of DNMT1 leads to hypomethylation of the CD47 promoter and increases the expression of CD47, a key inhibitor of macrophage phagocytosis. Elevated CD47 expression suppresses macrophage phagocytosis and promotes the survival of TMZ-treated GBM cells. The small molecule WIN 51708 disrupts the p-GSK3β-Y216-DNMT1 interaction, which stabilizes DNMT1, decreases CD47 expression, restores phagocytosis in vivo, and resensitizes tumors to TMZ. The GSK3β-DNMT1-CD47 axis was found to be conserved in a TMZ-resistant PDX model and in samples from patients with recurrent GBM, supporting its clinical translational value. Our findings underscore the potential of the combined administration of WIN 51708 and TMZ as a strategy to resensitize GBM tumors.

PMID 42667153
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PubMedExperimental neurology2026-08-29

EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.

Chen Lufei L, Lin Ruying R, Xu Yongpei Y, Lin Shiqi S et al.

Glioblastoma (GBM) exhibits profound metabolic and redox adaptation that supports tumor progression and therapeutic resistance. Here, we identify the glutamate transporter EAAT1 (SLC1A3) as a critical regulator of glutamate-dependent redox homeostasis in GBM. Analysis of TCGA and CGGA datasets showed that EAAT1 expression is elevated in GBM and associated with poor patient survival. Using CRISPR/Cas9-mediated EAAT1 knockout together with biochemical, imaging, transcriptomic, and in vivo approaches, we found that loss of EAAT1 altered extracellular and intracellular glutamate homeostasis, reduced intracellular glutamate, glutamine, and glutathione levels, and increased reactive oxygen species (ROS) accumulation. EAAT1 deficiency also suppressed oxidative phosphorylation and ROS-related programs and attenuated the Keap1/Nrf2/HO-1 antioxidant axis, accompanied by reduced GPX4 expression and increased lipid peroxidation. Furthermore, EAAT1 ablation downregulated glutamine synthetase and glutaminase, suggesting impaired glutamine-dependent anaplerotic metabolism. Glutamate supplementation partially restored Keap1/Nrf2/HO-1 pathway protein expression in EAAT1-knockout cells. Functionally, EAAT1 loss inhibited GBM cell proliferation and migration, enhanced sensitivity to oxidative stress and temozolomide (TMZ), and reduced tumor growth in xenograft models. Collectively, our findings establish EAAT1 as a key metabolic regulator linking glutamate transport to antioxidant defense and therapeutic response in GBM. Targeting EAAT1 may therefore represent a metabolic vulnerability for overcoming metabolic and redox adaptation and improving TMZ responsiveness in GBM.

PMID 42668078
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PubMedFrontiers in oncology2026-08-29

Metformin modulates the phenotypes of tumor-associated macrophages in glioblastoma in a context-dependent manner by promoting the homeostasis of macrophages.

Das Ashish A, Mahfooz Sadaf S, Wang Fei F, Guan Bingjie B et al.

Glioblastoma (GBM) remains the most aggressive primary adult brain cancer attributed to its immunosuppressive nature. Radiation therapy (RT) and concurrent temozolomide chemotherapy are the standard treatments for GBM. Emerging evidence indicates that metformin has potential as an anti-tumor agent that can reshape the immune landscape across various malignancies. We thus postulate that metformin may enhance the anti-tumor effect of RT by modulating the immunosuppressive milieu in GBM. We first explore multiple in vitro conditions, with or without pre-induction, and mimicked a tumor microenvironment to demonstrate a highly context-dependent effect of metformin on the polarization of bone marrow-derived macrophages (BMDMs). We then investigated the antitumor activity and immune-modulatory effects of metformin in combination with RT in GBM-bearing mice. The in vitro experiment showed that metformin inhibited the immunosuppressive effects of IL-4/IL-13 but also the immunostimulatory effects of Lipopolysaccharide (LPS) on BMDMs, demonstrating bidirectional immunomodulatory properties that depend on the baseline inflammatory stimulus. In tumor cell co-culture environment, metformin exhibited context-dependent immunoregulatory effects, predominantly promoting M1-associated activation. Notably, concurrent metformin treatment counteracted M2 polarization typically induced by the tumor microenvironment. In a high m-MCSF inducted M2-dominated condition, metformin preferentially shifted the highly polarized M2 phenotype toward an M1-like state in a time and dose-dependent manner but with limited promotion of M1 subtype maturation. RNAseq results on BMDM treated with metformin showed increased homeostasis. Metformin showed dose-dependent immunomodulatory effects when combined with RT in vitro. In syngeneic GBM mouse models, concurrent metformin + RT significantly prolonged survival and reduced tumor burden by reprogramming tumor-associated macrophages (TAMs), elevating intratumoral CD8+ T-cell infiltration and the CD8+/Treg ratio, increasing circulating CD8+ T cells, reversing RT-induced expansion of monocytic myeloid-derived suppressor cells (mMDSCs), and expanding CD4+ and CD8+ effector memory populations in peripheral blood. Metformin demonstrates inhibitory effects on M2 phenotype of macrophages. However, it is not a simple M2 inhibitor; instead, it functions primarily as a neutralizer of highly polarized macrophage states by promoting transcriptomic homeostasis. This context-dependent activity enables metformin to relieve the profoundly immunosuppressive TME of GBM to potentiate the anti-tumor effects of RT and by enhancing systemic immune memory.

PMID 42666173
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PubMedLa Clinica terapeutica2026-08-28

Multifaceted Temozolomide Toxicity in Glioma: Detection & Care.

Panda Ipsita I, Athiyamaan M S MS, Bharathi R Poovizhi P, Shamsudeen Manaal M

Gliomas are the most common malignant primary brain tumors, and Temozolomide (TMZ) remains a key component of their management. Despite its efficacy, TMZ is associated with adverse drug reactions (ADRs) that may affect quality of life and treatment compliance. This study evaluated the pattern and frequency of ADRs in South Indian glioma patients receiving TMZ, examined demographic associations, and reviewed management strategies. A retrospective observational study was conducted at KMC Hospital, Mangalore, India, over the past three years. Thirty-eight patients with histologically confirmed glioma who received oral TMZ were included. Data on demographics, tumor characteristics, treatment schedules, hematological and non-hematological ADRs, management approaches, and outcomes were extracted from medical records and analyzed using SPSS. The study population was predominantly male (68.4%), with a median age of 45.5 years. Grade 3 and Grade 4 gliomas accounted for 31.6% and 34.2% of cases, respectively. A total of 38 ADRs were documented. The most frequent ADRs were leukocytopenia (9.3%) and itching (9.3%). Management strategies included treatment deferral, dose reduction, antihistamines, nonsteroidal anti-inflammatory drugs, and blood transfusions. Most ADRs resolved without hospitalization. Skin-related reactions typically subsided within 4-14 days, whereas hematological toxicities such as neutropenia required longer recovery periods (22-75 days). The mortality rate was low (5.3%), suggesting effective ADR management. TMZ-related ADRs in glioma patients are diverse, underscoring the need for vigilant monitoring of both hematological and non-hematological toxicities. Individualized management and careful tracking of recovery times can improve treatment tolerance and patient quality of life.

PMID 42664125
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PubMedCancer treatment reviews2026-08-28

Glioblastoma and resistance to radiotherapy: role of cancer stem cells subpopulations, hypoxia and therapeutic strategies.

Sarrazin Elsa E, Valable Samuel S, Pérès Elodie A EA, Colloc'h Nathalie N et al.

Glioblastoma is the most aggressive primary brain tumor in adults, characterized by rapid progression, resistance to therapy, and inevitable recurrence. Despite standard treatment-surgical resection, X-ray radiotherapy, and temozolomide chemotherapy-prognosis remains poor. Growing evidence indicates that glioma stem cells (GSCs) and hypoxia drive this resistance and recurrence. This review examines distinct GSC subtypes: mesenchymal GSCs, the most aggressive and invasive; proneural GSCs, which are more radiosensitive but highly proliferative and contribute to recurrence; and slow-cycling GSCs, which, though less well understood, are of growing interest due to their activation and deactivation during radiotherapy or through as-yet-unknown mechanisms. Hypoxia, a hallmark of the glioblastoma microenvironment, maintains these stem cells in a dedifferentiated state. As a key regulator, hypoxia orchestrates radioresistance mechanisms and promotes stem-like cell persistence through processes such as epithelial-mesenchymal transition-like (EMT-like), proneural-mesenchymal transition (PMT), or the reprogramming of differentiated cancer cells into GSCs. The review concludes by highlighting therapeutic strategies under development to overcome radioresistance, including targeting GSCs, hypoxia, or employing alternative irradiation modalities beyond X-ray radiotherapy.

PMID 42659714
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PubMedBiology2026-08-27

Design and Biological Evaluation of ALKBH2 and ALKBH5 Inhibitors as Adjuvants to Temozolomide-Based Glioblastoma Treatment.

Rivara Mirko M, Malacrida Alessio A, Ghizzi Martina M, Bentivegna Angela A et al.

This study reports the design, synthesis, and biological evaluation of novel inhibitors targeting the epigenetic enzymes ALKBH2 and ALKBH5 as potential adjuvants to temozolomide therapy in glioblastoma. Given their critical role in DNA/RNA demethylation, tumor progression, and drug resistance, their inhibition represents a promising therapeutic strategy. Building on the previously identified lead compound MV1035, we employed structure-based drug design to develop new derivatives, including a second-generation series incorporating a fumarate hydrazide moiety to enhance binding affinity through interaction with both substrate- and cofactor-binding sites. Molecular docking studies predicted significantly improved binding for a set of new compounds but, due to multiple synthetic drawbacks, only a subset of the designed series was synthesized and evaluated biologically. MV3030 emerged as the most promising candidate. MV3030 demonstrated an inhibitory effect on ALKBH2 comparable to MV1035, also showing a more moderate inhibitory effect on ALKBH5. Notably, it exhibited intrinsic cytotoxicity in U87-MG cells and patient-derived glioma stem cells, whereas normal astrocytes exhibited markedly higher resistance to the treatment. Furthermore, MV3030 enhanced temozolomide efficacy and displayed favorable blood-brain barrier permeability both in silico and in vitro. Moreover, MV3030 modulated the FoxM1/Wnt/β-catenin axis. Overall, these findings identify MV3030 as a promising compound with the potential to overcome temozolomide resistance and improve glioblastoma treatment.

PMID 42651676
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