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Clinical Pharmacodynamics of Anticancer Drugs
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
Howard L. McLeod, William E. Evans
The toxicity and pharmacokinetics of the investigational anticancer drug amonafide were evaluated in 17 patients with refractory solid tumors.93 As amonafide is metabolized in part to N-acetyl-amonafide, N-acetylation phenotype was determined using caffeine as the substrate. Amonafide 300 mg/m2 was infused over 1 h daily for 5 d. Blood samples were obtained 45 min and 24 h after the end of the first daily infusion. The plasma amonafide AUC was estimated by a limited-sample strategy previously derived by the authors. Sixty and 40% of patients were slow and fast acetylators, respectively. Four of six fast acetylators had grade 3 to 4 leukopenia after amonafide treatment, significantly greater than slow acetylators (1/11 with grade 3 toxicity). Although the increased incidence in myelotoxicity is likely secondary to production of toxic metabolites of amonafide, 45-min and 24-h concentrations of N-acetyl-amonafide were greater in the fast acetylators. The estimated AUC of amonafide was not different between the two groups. While the explanation for these clinical findings is not currently clear, the potential importance of individualizing amonafide dosage based on N-acetylation phenotype is evident.
Pharmacology, Pharmacogenetics, and Pharmacoepidemiology: Three P’s of Individualized Therapy
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Linking the information obtained from the pharmacology and pharmacoepidemiology of a drug and the pharmacogenetics that describes the genetic makeup of the individual being treated with the drug is thus vitally important in developing an optimal approach to individualized therapy. The use of isoniazid in the treatment of tuberculosis is a good example. Epidemiological evidence shows that polymorphisms differ in frequency among ethnic and racial groups. This phenomenon was shown early on when interindividual and interethnic variations of efficacy and toxicity associated with isoniazid treatment was observed in a cohort of individuals with tuberculosis. The enzyme responsible for the metabolism of isoniazid is N-acetyltransferase, a phase II conjugating liver enzyme. Early studies of isoniazid revealed a bimodal distribution in its plasma concentration among individuals. High plasma concentrations were observed among individuals with the slow acetylator phenotype often resulting in peripheral nerve damage, while low plasma concentrations of isoniazid were observed among individuals with fast acetylator phenotype and were not affected (17). Studies have shown large variations in the incidence of the slow acetylator phenotype (inherited as an autosomal recessive trait) among different ethnic groups (40–70% of Caucasians and African Americans, 10–20% of Japanese, and more than 80% of Egyptians) (18,19). Amonafide (20), a topoisomerase II inhibitor, is another substrate of N-acetyltransferase whose clinical development has been hampered by highly variable and unpredictable toxicity caused, at least, in part, by interindividual differences in N-acetylation with fast acetylators experiencing greater myelosuppression than slow acetylators. This example illustrates both the importance of pharmacoepidemiological evidence in identifying and characterizing phenotypic variance to individual drugs and how the pharmacological effects of these drugs depend on pharmacogenetic determinants that define sensitivity to the drug, and ultimately describes the drug’s behavior.
N-acetyltransferase: the practical consequences of polymorphic activity in man
Published in Xenobiotica, 2020
Amonafide (5-amino-2-(2-dimethylaminoethyl)benzo(de)isoquinoline-1,3-dione; benzisoquinolinedione) is an antineoplastic agent belonging to the class of topoisomerase inhibitors and DNA intercalators (Gellerman, 2016). It has been investigated in several clinical trials for the treatment of various cancers including that of the breast and prostate and also acute myeloid leukemia (Andersson et al., 1987; Legha et al., 1987; Saez et al., 1989). The compound undergoes extensive biotransformation and several of these metabolites may be N-acetylated. The N-acetylated derivative of the parent compound is also a pharmacologically active molecule (Felder et al., 1987). In early studies it was reported that no N-acetylated metabolites could be detected in the urine from two out of seven patients who had received amonafide treatment, suggesting inter-individual differences in the metabolic handling of the drug (Felder et al., 1987).
UNBS5162 as a novel naphthalimide holds efficacy in human gastric carcinoma cell behaviors mediated by AKT/ERK signaling pathway
Published in Drug Development and Industrial Pharmacy, 2019
Hong-Hai Li, Xian-Xu Song, Bo Liu, Wen-Ping Yang
Naphthalimides could easily interact with various active targets in biological system and exhibit diverse biological activities including anticancer [20]. One of naphthalimides, amonafide has proceeded to clinical development for the treatment of advanced breast cancer [21]. Besides, elinafide, as one naphthalimide drug, is currently being used in clinical trials against solid tumors [13]. Given these findings, we believe that UNBS5162 can also be utilized for the treatment of cancer, such as gastric cancer. As expected, we first showed that UNBS5162 inhibited proliferation, invasion and migration abilities in SGC-7901 cells. Apoptosis is an evolutionarily conserved process by removing superfluous cells which are dangerous for the survival of the organism [22]. Autophagy is also an evolutionarily conserved process, distinct from apoptosis, that is multi-step lysosomal degradation in which long-lived proteins could be degraded by a cell [23]. Apoptosis and autophagy both play an important role in carcinogenesis [24]. As the next significant finding in current study, UNBS5162 promoted autophagy and apoptosis of SGC-7901 cells through assessing the level of key indices associated with autophagy and apoptosis. Mechanistically, AKT/ERK signaling pathway was involved in occurrences of these processes.
Have molecular hybrids delivered effective anti-cancer treatments and what should future drug discovery focus on?
Published in Expert Opinion on Drug Discovery, 2021
Jia and coworkers reported the synthesis and anti-proliferative potential of naphthalimide-ferrocene hybrids against four different cancer cell lines keeping Amonafide as the control. Most of the synthesized hybrids exhibited good cytotoxic activities with IC50s ranging from 4.33 to 10.52 µM. The most effective hybrid, 84, was 6–17 fold more potent than its precursor, thus demonstrating the synergistic effect between ferrocene and naphthalimide core in enhancing the cytotoxicity [123].