Dataset Information

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.

ABSTRACT: The structure of the anticancer drug capecitabine was redesigned to prevent metabolic conversion to 5-fluorouracil and its associated potentially fatal toxicities. The resulting cytidine analogue, pencitabine, is a hybrid of capecitabine and gemcitabine, another anticancer drug in clinical use. Preliminary biological evaluation revealed that pencitabine is cytotoxic in vitro in cell culture and orally active in vivo in a human xenograft test system. Pencitabine may mimic the known therapeutically advantageous combination of its parent drugs. Pencitabine is postulated to interfere with DNA synthesis and function by inhibiting multiple nucleotide-metabolizing enzymes and by misincorporation into DNA. Based on detailed mechanistic analyses and literature precedents, the hypothesis is put forward that the significant DNA damage caused by pencitabine may be accounted for by two additional effects not shown by the parent drugs: inhibition of DNA glycosylases involved in base excision repair and of DNA (cytosine-5)-methyltransferase involved in epigenetic regulation of cellular metabolism.

SUBMITTER: Kalman TI

PROVIDER: S-EPMC8919275 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.

Kalman Thomas I TI

ACS medicinal chemistry letters 20220221 3

The structure of the anticancer drug capecitabine was redesigned to prevent metabolic conversion to 5-fluorouracil and its associated potentially fatal toxicities. The resulting cytidine analogue, pencitabine, is a hybrid of capecitabine and gemcitabine, another anticancer drug in clinical use. Preliminary biological evaluation revealed that pencitabine is cytotoxic <i>in vitro</i> in cell culture and orally active <i>in vivo</i> in a human xenograft test system. Pencitabine may mimic the known ...[more]

PMID: 35300092

Similar Datasets

Project description:Objectives Fluoropyrimidine-based regimens have been investigated as the second line chemotherapy in patients with advanced pancreatic cancer refractory to gemcitabine. We conducted this systematic review and meta-analysis to evaluate the efficacy and safety profile of fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in such patients. Methods The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts were systematically searched. Randomized controlled trials (RCTs) that compared fluoropyrimidine combination therapy versus fluoropyrimidine monotherapy in patients with gemcitabine-refractory advanced pancreatic cancer were included. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate (ORR) and serious toxicities. Statistical analyses were performed by using Review Manager 5.3. Egger’s test was performed to assess the statistical evidence of publication bias by using stata 12.0. Results A total of 1183 patients from six randomized controlled trials were included for this analysis. Fluoropyrimidine combination therapy increased ORR [RR 2.82 (1.83–4.33), p<0.00001] and PFS [HR 0.71 (0.62–0.82), p<0.00001], without significant heterogeneity. Fluoropyrimidine combination therapy improved OS [HR 0.82 (0.71–0.94), p = 0.006], with significant heterogeneity (I2 = 76%, p = 0.0009). The significant heterogeneity might have been caused by the different administration regimens and baseline characteristics. Peripheral neuropathy and diarrhea were more common in the regimens containing oxaliplatin and irinotecan, respectively. No publication bias was detected by Egger’s tests. Conclusions Compared with fluoropyrimidine monotherapy, fluoropyrimidine combination therapy had a higher response rate and longer PFS in patients with gemcitabine-refractory advanced pancreatic cancer. Fluoropyrimidine combination therapy could be recommended in the second line setting. However, due to concerns about toxicities, the dose intensities of chemotherapy drugs should be carefully considered in patients with weakness.

Dataset Information

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.

Publications

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets