Low-dose total skin electron beam therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma.

BACKGROUND: Total skin electron beam therapy (TSEBT) combined with systemic therapy or maintenance treatment is a reasonable approach to enhance the remission rate and duration in mycosis fungoides (MF) and Sézary syndrome (SS). This study assesses the efficacy of oral bexarotene therapy after low-dose TSEBT for patients with MF and SS. METHODS: In this prospective observational study, we recruited MF/SS patients for treatment with low-dose total skin electron beam therapy (TSEBT) with or without bexarotene therapy to describe outcomes and toxicities. RESULTS: Forty-six subjects with MF or SS underwent TSEBT between 2016 and 2021 at our institute. Following TSEBT, 27 patients (59 %) received oral bexarotene treatment. The median follow-up was 13 months. The overall response rate (ORR) for the cohort was 85 %. The response rate was significantly higher with combined modality (CM) than TSEBT alone (96 % vs. 68 %, p = 0.03). Median progression-free survival (PFS) for the CM was 17 months versus five months following TSEBT alone (p = 0.001). One patient (4 %) in the retinoid group discontinued the bexarotene therapy because of adverse events. The administration of bexarotene therapy did not increase radiation-related toxicities. CONCLUSIONS: Response rate and progression-free survival might be improved with TSEBT in combination with oral bexarotene compared to TSEBT alone.

Novel Nicotinonitrile Derivatives Bearing Imino Moieties Enhance Apoptosis and Inhibit Tyrosine Kinase.

BACKGROUND: Fused heterocyclic containing pyrazolopyridine systems have several medicinal activities including cytotoxic and carcinostatic activities. OBJECTIVE: To investigate the antiproliferative activity and associated mechanism(s) of a novel series of nicotinonitrile derivatives. METHOD: The series has been synthesized by the reaction of hydrazonoyl chlorides with each of 4-(4- methoxyphenyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and 2-amino-4-(4- methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile in dioxane in basic medium. The assigned structures for each of the new products were identified via elemental and spectral data. Moreover, the cytotoxic activity for some selected products was screened. RESULTS: Derivatives 5g, 7i, 8 and 9 had their IC50 at ~ 1-3 µM and derivatives 7b, 7d, and 7f were similar to 5- fluorouracil and had their IC50 at ~ 5 µM against breast (MCF-7) and colon (HCT-116) cell lines. All derivatives were specific in action and safe to normal fibroblasts (WI38). Only derivative 9 caused some toxicity but at high concentration of 93 µM. These derivatives exerted strong antiproliferative activity through inducing intrinsic apoptosis as indicated from the significant induction of caspases 9 and 3 by 3-6 folds in colon cells and/or inhibiting tyrosine kinase (TK) and hence arresting the cell cycle. CONCLUSION: Compounds 8 and 5g were the most potent anticancer agents inhibiting the TK by 86 and 89% and their IC50 of the enzyme were 311 and 352 nM, respectively. We believe that these derivatives deserve further investigation and these chemical moieties could offer promising anticancer drugs.