Chemotherapeutic dosing implicated by pharmacodynamic modeling of in vitro cytotoxic data: a case study of paclitaxel

AbstractConventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing. Based on in vitro cytotoxic data, we developed a cellular PD model, which assumed that tumor cells were generally comprised of two subpopulations that were susceptible to either concentration- or time-dependent cytotoxicity. The developed PD model exhibited high flexibility to describe diverse patterns of cell survival curves. Integrated with a PK model, the cellular PD model was further extended to predict and compare the anti-tumor effect of paclitaxel in two dosing regimens: multiple MTD bolus and continuous constant infusion (an extreme LDHF). Our simulations of paclitaxel in treatment of three types of cancers were consistent with clinical observations that LDHF yielded higher patient efficacy than MTD. Our further analysis suggested that the ratio between drug steady-state concentrations and its...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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Source: Anti-Cancer Agents in Medicinal Chemistry - Category: Cancer & Oncology Authors: Tags: Review article Source Type: research
This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research
Publication date: Available online 21 January 2020Source: Chemico-Biological InteractionsAuthor(s): Brian C. Geohagen, Daniel A. Weiser, David M. Loeb, Lars U. Nordstroem, Richard M. LoPachinAbstractCisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs (e.g., carboplatin, oxaliplatin) are highly effective and widely used in the treatment of solid tumors in both pediatric and adult patients. Although considered to be life-saving as a cancer treatment, Pt-based drugs frequently result in dose-limiting toxicities such as chemotherapy-induced peripheral neuropathies (CIPN). Specifically, irreversible damage to o...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research
Publication date: Available online 21 January 2020Source: Chemico-Biological InteractionsAuthor(s): Xiao-liang Liu, Huan-qiu Liu, Ji Li, Cui-ying Mao, Xin Zhao, Jin-ting HeAbstractEpigenetic variations can play remarkable roles in different normal and abnormal situations. Such variations have been shown to have a direct role in the pathogenesis of various diseases either through inhibition of tumor suppressor genes or increasing the expression of oncogenes. Enzymes involving in epigenetic machinery are the main actors in tuning the epigenetic-based controls on gene expressions. Aberrant expression of these enzymes can trig...
Source: Chemico Biological Interactions - Category: Biochemistry Source Type: research
New J. Chem., 2020, Accepted Manuscript DOI: 10.1039/C9NJ03817E, PaperAlberto Ongaro, Giovanni Ribaudo, Emmanuelle Braud, M élanie Etheve-Quelquejeu, Michele De Franco, Christiane Garbay, Luc Demange, Nohad Gresh, Giuseppe Zagotto Abstract: In oncology, some DNA intercalating agents have been used in chemotherapy for years to eradicate cancer cells, but these drugs generally suffered from a lack of selectivity for malignant... The content of this RSS Feed (c) The Royal Society of Chemistry
Source: RSC - New J. Chem. latest articles - Category: Chemistry Authors: Source Type: research
Chemoradiotherapy as an alternative to surgery can be offered to patients affected by loco-regionally advanced head and neck cancer (HNC). Induction chemotherapy is a valid option, supported by few positive trials, but its real efficacy is still a matter of debate. The standard regimen for induction chemotherapy in Europe is a combination of docetaxel (75 mg/m2) and reduced dose doses of cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 day, for five consecutive days) (TPF). It is less toxic and more effective than the historical therapy PF (cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/day for five consecutive days). ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsThis study reveals inconsistencies regarding adherence to the recommendations of the ESMO guidelines for the management of mCRC in Spain. Improved adherence to the standard practice described in such guidelines for the determination of RAS and BRAF mutation statuses and the use of targeted therapies in first-line treatment should be considered to guarantee that patients can benefit from the best therapeutic approaches available.
Source: Clinical and Translational Oncology - Category: Cancer & Oncology Source Type: research
ConclusionIn this experimental model, combined therapy with chemotherapy and Adv-shPGK1 improves control of PM of gastric origin as compared to chemotherapy alone and might counteract chemoresistance of PM. A systemic toxicity of Adv-shPGK1 cannot be excluded.
Source: European Journal of Surgical Oncology (EJSO) - Category: Surgery Source Type: research
This study reviewed medical records of patients with gastric cancer who received XPT(capecitabine/cisplatin/trastuzumab) therapy containing cisplatin. Patients received either the conventional or short hydration regimen. Nephrotoxicity was compared between these two regimens by monitoring the serum creatinine. Out of the 26 total patients, 19 received the conventional regimen while 7 received the short hydration regimen. There was a higher nephrotoxicity was observed in the group receiving the conventional regimen (42.1%, 8/19) as compared to the short hydration regimen (0%, 0/7). There was a statistically significant diff...
Source: Journal of Chemotherapy - Category: Cancer & Oncology Tags: J Chemother Source Type: research
This study investigated the relationships between EGFR mutations and skin rash. We first compared skin rash grades between different mutations, then tested factors possibly affecting skin rash by multivariate analysis. The main outcome measure was the significant difference in incidence of skin rash between each group with different mutations. Our study suggested that the risk of skin rash is low in patients with exon 19 deletion mutations who are taking EGFR-TKIs, whereas it is high in those with exon 21 point mutations. These results will be useful indicators for instructions regarding daily examinations, skin care, and ...
Source: Journal of Chemotherapy - Category: Cancer & Oncology Tags: J Chemother Source Type: research
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