Oxaliplatin delivery via chitosan/vitamin E conjugate micelles for improved efficacy and MDR-reversal in breast cancer.

A bioinspired chitosan/vitamin E conjugate (Ch/VES, 1:4) was synthesized, optimized based on chitosan's molecular weight (15, 300 kDa), and was assembled to entrap oxaliplatin (OXPt). 1H NMR, infrared spectroscopy, chromatography, X-ray photoelectron spectroscopy, X-ray diffraction, drug release, hemolysis, and stability studies were performed to characterize OXPt@Ch/VES micelles. The therapeutic efficacy of the micelles was tested in vitro in ER+/PR+/HER2- and triple-negative sensitive/resistant breast cancer cells, MCF-7 and MDA-MB-231 via cellular uptake, cytotoxicity, nuclear staining, DNA fragmentation, mitochondrial membrane potential, ROS generation, apoptosis, and cell cycle assays and in vivo using 4T1(Luc)-tumor-bearing mice. OXPt@Ch/VES Ms exhibited decreased IC50 towards MCF-7, MDA-MB-231 (sensitive/resistant) than OXPt. OXPt@Ch/VES Ms caused extensive DNA damage, mitochondrial depolarization, apoptosis, and cell-growth arrest (G2/M). OXPt@Ch/VES Ms treatment retarded tumor growth significantly, prolonged survival, and decreased nephrotoxicity than OXPt. The OXPt@Ch/VES Ms could serve as a potential nanomedicine to overcome conventional OXPt-mediated drug resistance/nephrotoxicity in breast cancer.

Effects of route of administration on neural exposure to platinum-based chemotherapy treatment: a pharmacokinetic study in rat.

The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.

Conjugation of oxaliplatin with PEGylated-nanobody for enhancing tumor targeting and prolonging circulation.

Oxaliplatin is a platinum-based drug used in clinic for cancer chemotherapy. Despite of its success, the non-selective effect on normal cells causes severe side-effects and hampers its applications. Targeted delivery of oxaliplatin to cancer cells is an effective approach to enhance drug efficacy and reduce adverse effect. In this work, the Pt(IV) prodrug of oxaliplatin has been conjugated to poly(ethylene glycol) (PEG) modified nanobody in order to achieve tumor targeting as well as improved circulation in vivo. The Pt(IV) prodrug was site-specifically linked to an anti-epidermal growth factor receptor (EGFR) nanobody, so that the drug can be accumulated more pronounced in EGFR positive tumor cells than in normal cells. The effect of different length of PEG on the drug circulation has been investigated, while the fusion of anti-albumin nanobody was used for comparison. The result demonstrates that the prolonged drug circulation significantly increases the in vivo drug efficiency of the oxaliplatin-nanobody conjugate.

Laser/GSH-Activatable Oxaliplatin/Phthalocyanine-Based Coordination Polymer Nanoparticles Combining Chemophotodynamic Therapy to Improve Cancer Immunotherapy.

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.

L-tetrahydropalmatine reduces oxaliplatin accumulation in the dorsal root ganglion and mitochondria through selectively inhibiting the transporter-mediated uptake thereby attenuates peripheral neurotoxicity.

Oxaliplatin (OXA) is a third-generation platinum drug; however, its application is greatly limited due to the severe peripheral neurotoxicity. This study aims to confirm the transport mechanism of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in the uptake of OXA in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L-THP (1-100 µM) reduced OXA (40 µM) induced cytotoxicity in MDCK-hOCT2 (Madin-Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, Co-administration of L-THP (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week, iv or ig) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week, iv) induced peripheral neurotoxicity and reduced the platinum concentration in the DRG. Whereas, L-THP (1-100 µM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 µM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.

Characterization and Pharmacokinetic Evaluation of Oxaliplatin Long-Circulating Liposomes.

The clinical efficacy of Oxaliplatin (L-OHP) is potentially limited by dose-dependent neurotoxicity and high partitioning to erythrocytes in vivo. Long-circulating liposomes could improve the pharmacokinetic profile of L-OHP and thus enhance its therapeutic efficacy and reduce its toxicity. The purpose of this study was to prepare L-OHP long-circulating liposomes (L-OHP PEG lip) by reverse-phase evaporation method (REV) and investigate their pharmacokinetic behavior based on total platinum in rat plasma using atomic absorption spectrometry (AAS). A simple and a sensitive AAS method was developed and validated to determine the total platinum originated from L-OHP liposomes in plasma. Furthermore, long-circulating liposomes were fully characterized in vitro and showed great stability when stored at 4°C for one month. The results showed that the total platinum in plasma of L-OHP long-circulating liposomes displayed a biexponential pharmacokinetic profile with five folds higher bioavailability and longer distribution half-life compared to L-OHP solution. Thus, long-circulating liposomes prolonged L-OHP circulation time and may present a potential candidate for its tumor delivery. Conclusively, the developed AAS method could serve as a reference to investigate the pharmacokinetic behavior of total platinum in biological matrices for other L-OHP delivery systems.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

BACKGROUND AND OBJECTIVES: Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. METHODS: Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. RESULTS: The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. CONCLUSION: In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer.

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3 h prior to the start of a 4 h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7 L and 30.0 µg·h/mL, respectively. A dose reduction of L-OHP by 30%-50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.

Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy.

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg-1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer.

OBJECTIVE: The anticancer efficacy of orally administered chemotherapeutics is often constrained by low intestinal membrane permeability and oral bioavailability. In this context, we designed a solid oral formulation of oxaliplatin (OP), a third-generation cisplatin analog, to improve oral bioavailability and investigate its application in metronomic chemotherapy. METHODS: An ion-pairing complex of OP with a permeation enhancer, N α-deoxycholyl-l-lysyl-methylester (DLM), was successfully prepared and then mixed with dispersing agents (including poloxamer 188 and Labrasol) to form the solid, amorphous oral formulation OP/DLM (OP/DLM-SF; hereafter, ODSF). RESULTS: The optimized powder formulation was sized in the nanoscale range (133±1.47 nm). The effective permeability of OP increased by 12.4-fold after ionic complex formation with DLM and was further increased by 24.0-fold after incorporation into ODSF. ODSF exhibited respective increases of 128% and 1010% in apparent permeability across a Caco-2 monolayer, compared to OP/DLM and OP. Furthermore, inhibition of bile acid transporters by actinomycin D and caveola-mediated uptake by brefeldin in Caco-2 cell monolayers reduced the apparent permeability values of ODSF by 58.4% and 51.1%, respectively, suggesting predominant roles for bile acid transporters and caveola-mediated transport in intestinal absorption of ODSF. In addition, macropinocytosis and paracellular and transcellular passive transport significantly influenced the intestinal permeation of ODSF. The oral bioavailabilities of ODSF in rats and monkeys were 68.2% and 277% higher, respectively, than the oral bioavailability of free OP. In vivo analyses of anticancer efficacy in CT26 and HCT116 cell-bearing mice treated with ODSF demonstrated significant suppression of tumor growth, with respective maximal tumor volume reductions of 7.77-fold and 4.07-fold, compared to controls. CONCLUSION: ODSF exhibits therapeutic potential, constituting an effective delivery system that increases oral bioavailability, with applications to metronomic chemotherapy.

Diversity of dose-individualization and therapeutic drug monitoring practices of platinum compounds: a review.

Introduction: Platinum-derived drugs are commonly used for the treatment of solid tumors. The differences in chemical structures of these molecules lead to different pharmacological properties, in terms of indication, efficacy, and toxicity. Their pharmacokinetics (PK) differ according to their respective renal elimination and have led to many studies investigating their dose optimization. Area covered: This review attempts to summarize and compare PK and pharmacodynamics of cisplatin, carboplatin, and oxaliplatin, with an emphasis on differences of dose calculations and opportunities for therapeutic drug monitoring (TDM) in various patient populations. Expert opinion: Although cisplatin and carboplatin can be considered as analogs since they share the same DNA interacting properties, the slower hydrolysis of the latter results in a better safety profile. Carboplatin is the only drug in oncology to be administrated according to a target area under the curve of concentration versus time, considering that its PK variability is almost fully explained by renal function, not by body size. This enables individual dosing based on predicted carboplatin clearance (along with patients renal characteristics) or on actual clearance with TDM, especially in a high-dose protocol.

Long-Circulating Thermosensitive Liposomes for the Targeted Drug Delivery of Oxaliplatin.

INTRODUCTION: Oxaliplatin (L-OHP) is a well-known third-generation platinum anticancer drug with severe systemic- and neuro-toxicity. The main objective of the current research was to develop a targeted long-circulating thermosensitive smart-release liposome (LCTL) system for better therapeutic efficacy and less toxicity. METHODS: The reverse-phase evaporation method (REV) was used to prepare L-OHP loaded LCTL (L-OHP/LCTL). The physical characteristics were evaluated including encapsulation efficiency (EE), size, zeta potential and stability. The release behavior, cytotoxicity and in vivo evaluation were also carried out. RESULTS: EE of LCTL was around 25% with a uniform size distribution, and LCTL achieved almost complete release at 42°C while it was only 10% at 37°C. Moreover, the LCTL showed significantly higher cytotoxicity at 42°C than that at 37°C. The in vivo results indicated LCTL could target tumors and enhance retention for more than 24 h, thereby enhancing anti-tumor efficacy on 4T1-bearing mice. DISCUSSION: These results indicated that LCTL not only possessed a prolonged circulation time but it also enhanced accumulation and achieved selective release at the tumor sites. Conclusively, LCTL could serve as a promising carrier for oxaliplatin delivery to treat solid tumors.

Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics.

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.

Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.

Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.

Ibudilast for prevention of oxaliplatin-induced acute neurotoxicity: a pilot study assessing preliminary efficacy, tolerability and pharmacokinetic interactions in patients with metastatic gastrointestinal cancer.

PURPOSE: This prospective, open-label, sequential 'before vs. after' pilot study was conducted to provide preliminary efficacy and tolerability data for ibudilast in the prevention of oxaliplatin-induced neurotoxicity in patients with metastatic upper gastrointestinal or colorectal cancer. Any potential impact of ibudilast on oxaliplatin and 5-fluorouracil pharmacokinetics was also explored. METHODS: Participants were administered a chemotherapy cycle (FOLFOX or CapeOx), followed by a chemotherapy cycle with co-administration of ibudilast 30 mg b.i.d. p.o. Efficacy was assessed on Day 3 and end of cycle using the Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and additional clinical/patient-reported neurotoxicity measures. A population pharmacokinetic approach was used to determine oxaliplatin and 5-fluorouracil pharmacokinetics with and without ibudilast. RESULTS: Sixteen participants consented; 14 completed both chemotherapy cycles. Across all measures, the majority of participants experienced either an improvement or no worsening of neurotoxicity with ibudilast treatment. Based on OSNS assessments, acute neurotoxicity was unchanged in 12/14 participants and improved in 2/14 participants. The 90% confidence interval (CI) of the dose-normalised ratio of oxaliplatin AUC (90% CI 95.0-109%) and 5-fluorouracil AUC (90% CI 66.5-173%) indicated no significant impact of ibudilast on systemic exposure. CONCLUSION: This pilot study indicated ibudilast co-administration may improve or stabilise oxaliplatin-induced neurotoxicity. Given the expected worsening of symptoms in patients with continued chemotherapy, this represents a signal of effect that warrants further investigation. Pharmacokinetic analysis indicates ibudilast has no significant effect on oxaliplatin pharmacokinetics, and is unlikely to influence pharmacokinetics of 5-fluorouracil. CLINICAL TRIAL REGISTRATION: Trial registration number: UTN U1111-1209-0075 and ANZCTRN12618000232235 (registered 13/02/2018).

A recombinant platform to characterize the role of transmembrane protein hTMEM205 in Pt(II)-drug resistance and extrusion.

Platinum-coordination complexes are among the most effective chemotherapeutic drugs used in clinics for the treatment of cancer. Despite their efficacy, cancer cells can develop drug resistance leading to treatment failure and relapse. Cellular uptake and extrusion of Pt(ii)-complexes mediated by transmembrane proteins are critical in controlling the intracellular concentration of Pt(ii)-drugs and in developing pre-target resistance. TMEM205 is a human transmembrane protein (hTMEM205) overexpressed in cancer cells that are resistant to cisplatin, but its molecular function underlying - resistance remains elusive. We developed a low-cost and high-throughput recombinant expression platform coupled to in vivo functional resistance assays to study the molecular mechanism by which the orphan hTMEM205 protects against Pt(ii)-complex toxicity. Based on the original observation by the Rosenberg group, which led to the discovery of cisplatin, we performed quantitative analysis of the effects of Pt(ii)-coordination complexes on cellular growth and filamentation in E. coli cells expressing hTMEM205. By coupling our methods with Pt quantification and cellular profiling in control and hTMEM205-expressing cells, we demonstrate that hTMEM205 mediates Pt(ii)-drug export selectively towards cisplatin and oxaliplatin but not carboplatin. By mutation analysis, we reveal that hTMEM205 recognizes and allows Pt(ii)-extrusion by a putative sulfur-based translocation mechanism, thereby resulting in pre-target resistance. Thus, hTMEM205 represents a new potential target that can be exploited to reduce cellular resistance towards Pt(ii)-drugs.

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Wide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study.

PURPOSE: In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored. METHODS: Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations. RESULTS: Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04). CONCLUSION: In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.

Dose-Escalation and Pharmacokinetic Study Following a Single Dose of Oxaliplatin in Cancer-Bearing Dogs.

Oxaliplatin is more potent than cisplatin, lacks cross-resistance to other platinum agents, and has a favorable toxicity profile. This study's objective was to define the maximally tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin in cancer-bearing dogs. This was a prospective, single-patient-cohort, dose-escalation study of oxaliplatin in client-owned dogs with confirmed, spontaneous malignancy. A single infusion was administered; the starting dose was 50 mg/m2, with 10 mg/m2 escalation-increments if no DLT was documented, up to a maximum dose of 140 mg/m2. Plasma total platinum was measured at multiple timepoints and patients were monitored weekly. Ten dogs were enrolled in single-patient-cohort treatment levels up to the maximum level of 140 mg/m2. There were no DLTs, and the maximally tolerated dose was not determined. The area under the curve0-7 days for 100-140 mg/m2 ranged from 77,850 to 82,860 ng/mL × hr; the area under the curve0-4 hr for 50-140 mg/m2 was linear with dose (r2 = 0.639, P = .0055). The data suggest a single infusion of oxaliplatin is well tolerated in cancer-bearing dogs up to 140 mg/m2. There was good correlation between exposure and dose, while achieving plasma levels similar to therapeutic levels documented in humans.