The duocarmycin family is a group of potent cytotoxic agents originally isolated from the bacterium Streptomyces. This discovery has spurred significant interest due to duocarmycins’ unique chemical structures and powerful mechanism of action. This review comprehensively details the history of the duocarmycin family, the current understanding of their therapeutic potential, and the major clinical trials that have been conducted. Chemically, the duocarmycin family is characterized by a DNA-binding unit that confers specificity, a subunit-linking amide that positions the molecule within the DNA helix, and an alkylating unit that interacts with the DNA. This configuration allows them to bind selectively to the minor groove of DNA and alkylate adenine bases, a notable deviation from the more common guanine targeting performed by other alkylating agents. Duocarmycin’s mechanism of action involves the formation of covalent adducts with DNA, leading to the disruption of the DNA architecture and subsequent inhibition of replication and transcription. Recent advancements in drug delivery systems, such as antibody–drug conjugates (ADCs), have further elevated the therapeutic prospects of duocarmycin analogs by providing a promising mechanism for enhancing intracellular concentrations and selective tumor delivery. Preclinical studies have highlighted the efficacy of duocarmycin derivatives in various in vitro models, providing a strong foundation for translational research. However, further biological research is required to fully understand the toxicology of duocarmycin family members before it can be clinically relevant. The major focus of this review is to cache the major biologically relevant findings of different duocarmycin analogs as well as their biological shortcomings to propose next steps in the field of cancer therapy with these potent therapeutics.

Background: In the United States, often only tertiary centers offer cytoreductive surgery and heated intraperitoneal chemotherapy (CRS+HIPEC) for peritoneal metastases in advanced lower gastrointestinal malignancies. Growing evidence shows that Medicaid expansion under the Affordable Care Act (ACA) of 2010 enhanced healthcare access and outcomes. Objective: We sought to determine whether Medicaid expansion was associated with decreased all-cause mortality of lower gastrointestinal cancer patients following CRS+HIPEC. Methods: We analyzed data from the National Cancer Database (2010–2019) on lower gastrointestinal cancer patients who underwent CRS+HIPEC. Medicaid expansion, introduced under the ACA in 2010, extends health insurance to low-income adults. We categorized states by expansion timing: early (2010–2013), immediate (January 2014), late (after January 2014), or no expansion to assess the impact of Medicaid expansion on mortality using a multivariable Cox regression model. Results: Of the 1001 study patients, 671 (67%) were diagnosed in Medicaid expansion states. Grade and Medicaid expansion status were the only factors independently associated with overall survival on multivariable analysis. On average, patients in Medicaid expansion states experienced a 4% increase in annual survival compared with those in non-expansion states who had a 1% decrease in annual survival over the study period. Conclusions: Patients from states that had an early expansion of Medicaid and patients with lower-grade tumors had significantly better overall survival. Our study findings suggest that improved access to healthcare through Medicaid expansion was associated with increased survival rates of lower gastrointestinal cancer patients who undergo CRS+HIPEC for the treatment of peritoneal metastases.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor survival outcomes. This study evaluated the anticancer potential of seco-duocarmycin SA (seco-DSA), a potent DNA-alkylating agent, alone and in combination with proton radiation in human GBM cell lines. Human glioblastoma cell lines T98G and LN18 were treated with varying concentrations of seco-DSA, proton radiation doses (2, 4, or 8 Gy), or both. Proton irradiation was delivered with a 250-MeV beam. Clonogenic survival, cell proliferation, and cell cycle distribution were analyzed using colony formation and flow cytometry assays. Proteomic analysis of LN18 cells was performed by LC-MS/MS followed by bioinformatic pathway analysis. Statistical significance was determined using a two-tailed unpaired t-test (p ≤ 0.05), and Bliss synergy scores were calculated to assess treatment interactions. Combination therapy produced additive and synergistic inhibition of colony formation and enhanced G2/M phase arrest compared with either treatment alone. Apoptosis and necrosis increased modestly but did not fully account for observed cytotoxicity. Proteomic profiling revealed differential expression of proteins involved in DNA repair, apoptosis, and senescence, indicating that seco-DSA broadened radiation-induced stress responses. Seco-DSA potentiates the cytotoxic effects of proton radiation in GBM cells through enhanced clonogenic inhibition and modulation of cell cycle and DNA repair pathways. These findings support seco-DSA as a promising radiosensitizer for further preclinical evaluation.