Treatment of renal cell carcinoma
Inventors
HARALDSSON BOERJE, null • Haraldsson, Börje • Nilsson, Ulf • Buvall, Lisa • NYSTROEM JENNY, null • Nyström, Jenny
Assignees
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Publication Number
US-8053430-B2
Publication Date
2011-11-08
Expiration Date
Abstract
Methods are provided of treating renal cancer by administration of certain 3,3′,4,4′-tetrahydroxy-2,2′-bipyridine-N,N′-dioxide compounds, especially 3,3′,4,4′-tetrahydroxy-2,2′-bipyridine-N,N′-dioxide (Orellanine), using particular administration protocols and dosing regimens, as well as pharmaceutical compositions suitable for use in the treatment methods that are provided.
Core Innovation
The invention relates to a method for treating a patient suffering from renal cell carcinoma by administering a compound according to Formula I, including a pharmaceutically acceptable salt. The described compound scope specifies substituent options R1, R2, R3 and/or R4 and permits further substitution of C1–C6 alkyl/alkenyl/alkynyl/alkanol/alkenol/alkoxy/alkenoxy with groups selected from amino, mercapto, carboxy, phosphate and halo.
The renal toxin 3,3′,4,4′-tetrahydroxy-2,2′-bipyridine-N,N′-dioxide (Orellanine) is selectively taken up by renal tubular epithelial/cancer cells and induces delayed cell death. The document connects this selective uptake/retention in renal cancer cells with toxicity against human renal carcinoma cell lines, including SKRC-52, 786-0, SKRC-17, SKRC-7, and SKRC-21, together with dose-response toxicity and accumulation/retention in cells.
The disclosed cellular and molecular outcomes include growth arrest via inhibition of G1/S and G2/M checkpoints and apoptosis induction. The described markers include changes involving p21/Rb/cdc2, activation of p38 and ERK1/2, cleaved caspase-3, and upregulation of PUMA, FasL, and TNF-α. In vivo, the document reports xenograft eradication in athymic rats and decreased tumor burden after orellanine, together with longer-term safety observations in pigs and dogs, including notable kidney tubular damage with minimal non-renal tissue effects and a reported human advanced RCC case with complete eradication of renal clear cell carcinoma.
Claims Coverage
One independent claim is presented, with the core coverage centered on administering a Formula I compound or a pharmaceutically acceptable salt to reduce tumor size in a patient suffering from renal cell carcinoma. Dependent claims refine the Formula I substitution pattern, routes of administration, and dosing regimens.
Formula I compound administration for renal cell carcinoma treatment with tumor-size reduction
A method for treating a patient suffering from renal cell carcinoma by administering to the patient a compound according to Formula I, optionally with specified options for R1, R2, R3 and/or R4 and further substitution for the C1–C6 alkyl/alkenyl/alkynyl/alkanol/alkenol/alkoxy/alkenoxy groups, or a pharmaceutically acceptable salt thereof, wherein the treatment results in a reduction in tumor size.
Further limitation of R1–R4 to hydrogen
The method includes the further-defined substituent pattern where R1, R2, R3 and R4 are hydrogen.
Intravenous, subcutaneous, or intraperitoneal administration routes
The method is carried out by administering the compound intravenously, subcutaneously, or intraperitoneally.
Single-dose quantity range
The method includes administering the compound as a single dose ranging from about 1 mg/kg to about 100 mg/kg.
Two or more doses with per-dose quantity range
The method includes administering the compound in two or more doses, with each dose containing between about 1 mg/kg and about 20 mg/kg of the compound.
Sequential dosing interval of two to seven days
The method includes carrying out sequential doses at intervals of between two and seven days apart.
Overall claim coverage centers on treating renal cell carcinoma with a Formula I compound or a pharmaceutically acceptable salt to reduce tumor size, with dependent claim refinements addressing a specific R-group setting, allowable administration routes, and particular single-dose, multi-dose, and dosing-interval ranges.
Stated Advantages
Reduction in tumor size.
Complete eradication of renal clear cell carcinoma is reported in a human advanced RCC treatment described in the document.
Xenograft eradication in athymic rats with decreased tumor burden is reported.
Documented Applications
Treatment of renal cell carcinoma in a patient, including a described human case of advanced renal cell carcinoma/renal clear cell carcinoma with complete eradication.
Use of orellanine in xenograft models in athymic rats, with decreased tumor burden and xenograft eradication.
Longer-term safety observations after orellanine in pigs and dogs, noting kidney tubular damage with minimal non-renal tissue effects.
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