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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There are several examples of prodrugs designed to be activated by CYP family enzymes, mainly developed by academic groups. Duocarmycin is a DNA minor-groove alkylating agent that requires the presence of a hydroxyl group at a certain position within the molecule in order to become activated as an electrophile. Analogues of duocarmycin have been synthesized which lack the hydroxyl group and so are relatively non-toxic as they cannot covalently bind to DNA. However, upon encountering the CYP enzyme at the tumor site, the hydroxyl group is added. A rearrangement then occurs to produce an electrophilic cyclopropane moiety which can form a covalent bond to the N3-position of an adenine base within the minor groove of DNA, a highly cytotoxic event. Similarly, a novel agent Phortress, developed by Malcolm Stevens and colleagues at Nottingham University (UK), was designed to be activated by CYP family enzymes to give an intermediate that spontaneously fragments into DNA-damaging species. Phortress was evaluated in Phase I trials in the late 2000s but was not progressed to a lack of efficacy.
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Unlike other CYPs, CYP2W1 has a unique luminal orientation in the ER but still retains catalytic activity (Gomez et al. 2010). CYP2W1 catalyzes the oxidation of indole and shows monooxygenase activity toward 3-methylindole and chlorzoxazone, but not AA (Yoshioka et al. 2006). CYP2W1 metabolizes certain lipids including lysolecithin and their stereoisomers (Karlgren et al. 2006; Xiao and Guengerich 2012). CYP2W1 expressed in HEK 293 cells is active in the metabolism of indoline substrates and is able to activate AFB1 into a cytotoxic product (Gomez et al. 2010). Lysophospholipids including oleyl (18:1) lysophosphatidylcholine (lysolecithin), lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidylglycerol, lysophosphatidylethanolamine, and lysophosphatidic acid, but not diacylphospholipids, are substrates for CYP2W1 (Xiao and Guengerich 2012). CYP2W1-mediated epoxidation and hydroxylation of 18:1 lysolecithin are considerably more efficient than for the C18:1 free fatty acid. Tumor-sepcific CYP2W1 converts duocarmycin analogs to cytotoxic metabolites and kill the cancer cells via induction of DNA damage (Travica et al. 2013). This might allow the development of a novel combined therapy of colorectal cancer that would include a tumor-specific induction of CYP2W1 followed by the treatment with CYP2W1-activated prodrug. Both CYP2W1 and 2S1 catalyze the reductive activation of the anticancer prodrug AQ4N (banoxantrone) to the topoisomerase II inhibitor AQ4 (Nishida et al. 2010). In addition, CYP2W1 can bioactivate heterocyclic amines such as 2-amino-3,4-dimethylimidazo[4,5-f]quinoline and 2-amino-3methylimidazo[4,5-f]quinoline (Eun et al. 2010), suggesting a role for CYP2W1 in carcinogenesis.
The evolving therapeutic landscape of antibody–drug conjugates in breast cancer
Published in Expert Review of Anticancer Therapy, 2022
Nan Chen, Elena Michaels, Frederick Howard, Rita Nanda
Trastuzumab duocarmazine is a HER2-targeting ADC containing trastuzumab and duocarmycin bound by a cleavable linker. Duocarmycin is a highly cytotoxic DNA alkylating agent. Similar to T-DXd, the payload in SYD985 is membrane permeable and can exert a bystander effect on adjacent cells regardless of HER2 expression [25]. In the dose escalation portion of the phase 1 trial, those with both HER2-positive and HER-2 low breast cancer were enrolled; the studied also included both HR-positive and HR-negative disease. An objective response was seen in 16 out of 48 patients with HER2-positive breast cancer (33%) [26]. Additionally, 9 out of 32 patients with HER2-low, HR-positive breast cancer (28%) and 6 out of 15 patients with HER2-low, HR-negative breast cancer (40%) had an objective response to treatment. There was a manageable safety profile.12 The phase III TULIP trial is an ongoing study of HER2-positive metastatic breast cancer patients with disease progression either on T-DM1 or with two HER2-targeted therapies. Patients were randomly assigned to SYD985 versus physician’s choice of treatment. Preliminary data from the trial showed significant improvement in investigator assessed PFS for SYD985 compared to physician’s choice (6.9 months vs 4.6 months, p < .001) [27] The study drug was discontinued in 35.4% of patients secondary to adverse events, most often due to eye and respiratory disorders [27].
Characterizing and understanding the formation of cysteine conjugates and other by-products in a random, lysine-linked antibody drug conjugate
Published in mAbs, 2021
Difei Qiu, Yande Huang, Naresh Chennamsetty, Scott A. Miller, Michael Hay
The ADC used in this study is composed of a potent cytotoxic prodrug covalently linked with a human anti-CD70 antibody (IgG1). CD70 is expressed in renal cell carcinoma, leukemias, lymphomas, and other cancers. Both antibody and cytotoxic prodrug (duocarmycin analog) were produced by Bristol Myers Squibb Co. The frozen naked antibody was thawed and pooled in a reactor, then exchanged with thiolation buffer to adjust pH from 7.0 to 7.4, following by treatment with 2-IT (20.5 equivalent). The resulting solution was agitated for 90 min at 23°C. Upon completion, the thiolated antibody was reacted with cytotoxic prodrug at pH 5.5 in agitation for 60 min at 23°C. Finally, the crude conjugate was exchanged with formulation buffer (pH 6.0) and diluted to 10 mg/mL with DAR 2.5 ~ 3.0 and 98% monomeric purity as determined by SEC.
Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches
Published in Expert Review of Anticancer Therapy, 2022
Teodora Alexa-Stratulat, Mariana Pavel-Tanasa, Vlad-Andrei Cianga, Sabina Antoniu
On the other hand galactoconjugate form of navitoclax which in a recent study was demonstrated to have an improved senolytic index compared to the non-conjugated compound (ie specificity for senescent cells) thus protecting non-senescent cells. The conjugate was also found to be less toxic for platelets [121]. Furthermore when applied in combination with cisplatin in A549 lung cancer cells navitoclax galactoconjugate was found to increase the cytotoxicity of cisplatin [121]. Other similar approaches were tested for 5 fluorouracil or for duocarmycin [121].