Kahalalide compounds for use in cancer therapy

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The present invention relates to the use of kahalalide compounds in the treatment of cancer.

Nature is the origin of many effective medicines in oncology, like paclitaxel, adriamycin, etoposide, bleomycin, etc. In recent years the sea has proven to be an invaluable source for compounds displaying original chemical structures and interesting biological activity. Among the cytotoxic compounds from marine origin we can mention the ecteinascidins, didemnins, dolastatins, spisulosines, lamellarins, some of them being developed as antitumoural agents in clinical trials.

WO 02 36145 describes pharmaceutical compositions containing kahalalide F and new uses of this compound in cancer therapy.

See also Beijnen, J. H. et al., Drug Dev. Ind. Pharm. 2001, 27(8) 767–80: “Development of a lyophilized parenteral pharmaceutical formulation of the investigational polypeptide marine anticancer agent kahalalide F”; Beijnen, J. H. et al., Br. J. Clin. Pharmacol. 2002, 53(5), 543: “Bioanalysis of the novel peptide anticancer drug kahalalide F in human plasma by h.p.l.c. under basic conditions coupled with positive turbo-ionspray tandem mass spectrometry”; Beijnen, J. H. et al., PDA J. Pharm. Sci. Technol. 2001, 55(4) 223–9: “In vitro hemolysis and buffer capacity studies with the novel marine anticancer agent Kahalalide F and its reconstitution vehicle cremophor EL/ethanol”; Sparidans R. W. et al., Anticancer Drugs 2001, 12(7) 575–82: “Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F”.

In preclinical studies, kahalalide F has shown significant activity against solid tumour cell lines, and selectivity for, but not restricted to, prostate tumour cells, neuroblastomas, some primary sarcoma lines and tumour cells that overexpress the Her2/neu oncogene. In vitro exposure studies demonstrated that kahalalide F is not schedule dependent. Its mechanism of action is not yet elucidated, in vitro studies have shown activity of kahalalide F to cause cell swelling and ultimately death, see for example Garcia-Rocha M, Bonay P, Avila J., Cancer Lett. 1996 99(1) 43–50: “The antitumoural compound Kahalalide F acts on cell lysosomes”.

Preclinical in vivo studies determined that the maximum tolerated dose (MTD) of KF in female mice following a single bolus iv injection was to be 280 μg/kg. Whereas single doses just above the MTDiv were extremely toxic, with animals exhibiting signs of neurotoxicity followed by death, 280 μg/kg KF could be administered repeatedly, according to a once daily times five schedule, without any apparent evidence of acute toxicity. See Supko, F. et al., Proceedings of the 1999 AACR NCI EORTC International Conference, abstract 315: “Preclinical pharmacology studies with the marine natural product Kahalalide F”.

During preclinical studies kahalalide F exhibited low cardiac and skeletal muscle toxicities and also low myeolotoxicity. In mice, the main toxicities found were tubular nephrotoxicity and CNS (central nervous system) neurotoxicity, and hints of hepatotoxicity. Therefore the expected toxicities were renal and neurologic with a marked threshold. As mentioned before, whereas MTD had no lethality, doses slightly over MTD showed high lethality.

It is an object of the present invention to provide new, improved forms of treatment using kahalalide compounds showing clinical benefit.

In particular, it is an object of the invention to provide dosages and schedules of kahalalide compounds that can be used for cancer therapy in humans, avoiding toxicities while maintaining the desired antineoplastic effects.

It is another object of the present invention to provide new uses in cancer therapy for the kahalalide compounds, in particular for kahalalide F.

It is yet another object of the invention to provide new products containing kahalalide compounds, in particular kahalalide F, for administration in the treatment of cancer.

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