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Antineoplastic activity of GP-2250 in-vitro and in mouse xenograft models
R Duane Sofia1, Kathryn M Martin2, James C Costin3
1Head Nonclinical Research and Development Panavance Therapeutics.
Abstract:
This study examined the antineoplastic effects of GP-2250 (misetionamide), an oxathiazine derivative with broad activity, in multiple cancer cell lines and mouse xenograft models. Antineoplastic activity of GP-2250 was tested in >300 cancer cell lines using the OncoPanel cytotoxicity assay. GP-2250 activity was further tested in mouse xenograft models, in which GP-2250 or vehicle (10 ml/kg) was administered daily for 28 days by intraperitoneal injection in the lower right abdomen of CrTac:NCR-Foxn1nu mice with tumor volumes of 100 to 200 mm 3 . In the in-vitro models, GP-2250 increased cytotoxicity readings with IC50 and EC50 as well as indications of cell cycle blockage in pancreatic and ovarian cell lines. In mouse xenograft models, a reduction of 30-40% in tumor volume occurred in the GP-2250 group versus the vehicle group. On the final day of the study, tumor progression was significantly reduced in 4 tumor types: HT-29 in the GP-2250 500 and 1000 mg/kg groups, SKOV-3 in all GP-2250 treatment groups, Cal-27 in the GP-2250 1000 mg/kg group, and Hs-695T in the GP-2250 250 and 1000 mg/kg groups. Tumor regression in Cal-27 tumors was dose-dependent. GP-2250 demonstrated cytotoxic activity in vitro and reduced the tumor volume in a variety of human cancer cell lines in a xenograft mouse model. Given these results, as well as evidence of synergism with other anticancer drugs, GP-2250 shows promise as a new therapeutic agent for treating human cancers and is being evaluated in a phase 1 dose-escalation study (NCT03854100).
Insights
GP-2250 (misetionamide) demonstrated significant antineoplastic effects, reducing tumor volume in mouse models and increasing cancer cell cytotoxicity in vitro. This oxathiazine derivative shows promise as a novel therapeutic agent for various human cancers.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Cancer Research
Background:
- The development of novel antineoplastic agents is crucial for improving cancer treatment outcomes.
- Oxathiazine derivatives represent a class of compounds with potential anticancer activities.
- GP-2250 (misetionamide) is an oxathiazine derivative investigated for its broad-spectrum activity.
Purpose of the Study:
- To evaluate the antineoplastic effects of GP-2250 in a comprehensive panel of cancer cell lines.
- To assess the efficacy of GP-2250 in reducing tumor growth in preclinical mouse xenograft models.
- To determine the potential of GP-2250 as a new therapeutic agent for human cancers.
Main Methods:
- In vitro screening of GP-2250's cytotoxicity against over 300 cancer cell lines using the OncoPanel assay.
- In vivo studies involving daily intraperitoneal administration of GP-2250 or vehicle to mice bearing human cancer xenografts for 28 days.
- Assessment of tumor volume reduction, tumor progression inhibition, and dose-dependent effects in xenograft models.
Main Results:
- GP-2250 exhibited cytotoxic activity in vitro, with notable IC50 and EC50 values and cell cycle blockage in pancreatic and ovarian cell lines.
- Significant tumor volume reduction (30-40%) was observed in GP-2250 treated mice compared to the vehicle group.
- GP-2250 demonstrated significant inhibition of tumor progression in HT-29, SKOV-3, Cal-27, and Hs-695T xenograft models, with dose-dependent regression in Cal-27 tumors.
Conclusions:
- GP-2250 possesses significant in vitro cytotoxic and in vivo tumor-reducing capabilities against a variety of human cancers.
- The observed efficacy in xenograft models, coupled with evidence of synergistic effects with other anticancer drugs, supports GP-2250's therapeutic potential.
- GP-2250 is a promising candidate for cancer therapy and is currently under evaluation in a Phase 1 clinical trial (NCT03854100).
