Mustargen (mechlorethamine)

To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent...ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

In vivo experiments prove nanomicelle Mech02-HA NPs is able to activate immune memory effects and raise the persistence of anti-tumor immunity. In summary, this study for the first time to introduce the arsenic(III) pharmacophore as an enhanced ICD effect initiator into nitrogen mustard, providing insights for the development of efficient multimodal tumor therapy agents.

Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.

Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation...At the molecular level, both compounds deregulate the expression and phosphorylation of β-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through β-catenin/Akt/mTOR signaling pathways.

To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time...In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

After 8 cycles, patients with VGPR remission receive Chlorambucil 6mg D1-4,15-18, dexamethasone 20mg D1-4,15-18, cyclophosphamide 300mg, D1-4,15-18 for 4cycles, others receive Zanubrutinib as maintenance. These results demonstrate that zanubrutinib, dexamethasone and or not cyclophosphamide are quickly effective in the treatment of WM, with more deeper response and less toxicity, maybe treatment discontinued by combining with cyclophosphamide after deep remission. Comments*The regimen of ZD: Zanubrutinib 240mg d1-28, dexamethasone 20mg D1-4,15-18. Patients more than 75 years old, Zanubrutinib 160mg d1-28, dexamethasone 10mg D1-4,15-18.

Chlormethine (CL), also known as mechlorethamine, chlorethazine, mustine, HN2, caryolysine and embichin, is a synthetic deoxyribonucleic acid-alkylating agent that was used as a chemical weapon (mustard gas) during the First World War. CL has since been developed as a topical treatment for MF and prescribed as such for over 70 years. This review aims to summarize the current knowledge regarding the mechanism of action of CL in the cutaneous micro-environment, in the specific context of MF treatment.

MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.

The combination of doxorubicin (Adriamycin) and cyclophosphamide, referred to as AC chemotherapy, is commonly used for the clinical treatment of breast and other cancers...Herein, we demonstrate that anthracyclines with aldehyde-reactive primary and secondary amines form covalent Schiff base adducts with AP sites in a 12-mer DNA duplex, calf thymus DNA, and MDA-MB-231 human breast cancer cells treated with nor-nitrogen mustard and the anthracycline mitoxantrone. The anthracycline-AP site conjugates are characterized and quantified by mass spectrometry after NaB(CN)H or NaBH reduction of the Schiff base. If stable, the anthracycline-AP site conjugates represent bulky adducts that may block DNA replication and contribute to the cytotoxic mechanism of therapies involving combinations of anthracyclines and DNA alkylating agents.

A single-day dose of 180 mg/m of bendamustine every 28 days was safe and well tolerated in pediatric patients. While age accounted for 23% of inter-individual variability observed in bendamustine clearance, the differences did not affect the safety and tolerability of bendamustine in our patient population.

Here, a hypoxia-activated mitochondria-accumulated Ru(II) polypyridyl prodrug functionalized with conjugated azo (Az) and nitrogen mustard (NM) functionalities, RuAzNM, is reported...This unique strategy allows controlled multimodal theranostics to be realized in hypoxic cells and multicellular spheroids, making RuAzNM a highly selective and effective cancer-cell-selective theranostic agent (IC = 2.3 ?M for hypoxic HepG2 cancer cells versus 58.2 ?M for normoxic THL-3 normal cells). This is the first report of a metal-based compound developed as a multimodal theranostic agent for hypoxia.

In this work, fifteen 4-anilinoquinazoline derivatives bearing nitrogen mustard or hemi mustard moieties were designed and synthesized as dual EGFR-DNA targeting anticancer agents...Compound 6g emerged as the most potent derivative against mutant-type H1975 cells with IC value of 1.45 μM, which exhibited 4-fold stronger potency than Chl/Gef (equimolar combination of chlorambucil and gefitinib)...Molecular docking was also performed to gain insights into the ligand-binding interactions of 6g inside EGFR and EGFR binding sites. Moreover, 6g efficiently inhibited tumor growth in the H1975 xenograft model without side effects.

P1; Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

COTI-2 activity correlated with nitrogen mustard, cisplatin and gemcitabine, doxorubicin and selumetinib, with a trend for APR-246 with doxorubicin. Cisplatin synergy is consistent with P53's role in DNA damage. Different mechanisms of action may underlie disease specificity and offer better disease targeting.

To increase the DNA damage activity in tumor cells in vivo, we compared ZR2002 with two of its 6-N,N-disubstituted analogs: "JS61", with a nitrogen mustard function at the six-position of the quinazoline ring, and "JS84", with an N-methyl group... The results in toto suggest that intratumoral concentrations of intact ZR2002 are correlated with the highest inhibition of P-EGFR and induction of DNA damage in vivo. ZR2002 may well represent a good drug candidate for the treatment of EGFR-expressing osteosarcoma.

Preserving the original carbonyl group, molecules with potent PARP1 inhibitory activities were derived by introduction of hydrazide and aromatic nitrogen mustard groups. Further analysis revealed the effects of C2 in induction of G2/M phase cell cycle arrest and promotion of apoptosis. Collectively, the olaparib-chlorambucil hybrid molecule (C2) could be utilized as a lead compound for further drug design.

P1; Trial completion date: May 2024 --> Dec 2024 | Trial primary completion date: May 2024 --> Dec 2024

Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia.

P2, N=30, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Nov 2022 --> Aug 2022 | Trial primary completion date: Nov 2022 --> Aug 2022

AST-3424 is a prodrug of a potent nitrogen mustard, which targets the tumor by its specific and selective mode of activation and results in the concentration of the drug in the tumor and plays a higher intensity of antitumor effect with reduced side effects...The inhibition of AST-3424 was significantly higher than OXA, 5-Fu, Sor (sorafenib), and Apa (apatinib) in both HCC cells...The in-vitro studies revealed that AST-3424 in combination with both OXA and 5-Fu showed an increased antitumor effect, and the combination with OXA resulted in a synergistic effect. Together with the in-vitro results, additional in-vitro and in-vivo studies are warranted to further certify its antitumor effects and explore more potential antitumor mechanisms.

Here, we show that functionalization of the 4-arylidene position of the fluorescent curcumin scaffold with an aryl nitrogen mustard provides a stable Hck inhibitor which binds specifically to the inactive conformation of Hck, similar to type-II kinase inhibitors that are less promiscuous...We demonstrate that the cytotoxicity may be mediated via inhibition of the SFK signalling pathway in triple-negative breast cancer and murine macrophage cells. Our data suggest that curcumin is a modifiable fluorescent scaffold to develop selective kinase inhibitors by remodelling its target affinity and cellular stability.

Treatment included chemotherapy(containing nitrogen mustard phenylbutyrate, fludarabine, cyclophosphamide), proteasome inhibitor regimens, rituximab regimens and immunomodulator regimens. Conclusion These results demonstrate that zanubrutinib and dexamethasone are quickly effective in the treatment of WM, with more deeper response and less toxicity.

Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated.

In this review we exposed the current knowledge regarding chemotherapy-induced oxidative stress and mitochondrial dysfunction to cause cognitive impairment.We especially focused on the antineoplastic agent (ADRIAMYCIN, CYCLOPHOSPHAMIDE), platinum group agent CISPLATIN, antimetabolite agents (METHOTREXATE), and nitrogen mustard agent (CARMUSTINE) which increase oxidative stress and inflammatory markers in the PNS (peripheral nervous system) as well as the central nervous system. We also highlight the behavioural and functional changes in the brain.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized...In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

A novel nitrogen mustard CBISC has been synthesized and evaluated as an anticancer agent...Further, in vivo studies revealed that CBISC is well tolerated in healthy mice and exhibited significant in vivo tumor growth inhibition properties in WiDr and MIAPaCa-2 xenograft models. These studies illustrate the potential utility of CBISC as an anticancer agent.