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Antisense oligonucleotides directed to ribonucleotide reductase r2 and uses thereof in the treament of cancer

a technology of ribonucleotide reductase and antisense oligonucleotides, which is applied in the field of cancer treatment, can solve the problems of ribonucleotide reductas

Inactive Publication Date: 2006-10-26
LORUS THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] In accordance with another aspect of the present invention, there is provided an antisense oligonucleotide of between 7 and 100 nucleotides in length comprising at least 7 consecutive nucleotides from SEQ ID NO:1 for use in combination with one or more chemotherapeutic agents in the treatment of cancer in a mammal in need of such therapy.
[0008] In accordance with another aspect of the present invention, there is provided an antisense oligonucleotide of between 20 and 100 nucleotides in length comprising the sequence as set forth in SEQ ID NO:1 for use in combination with one or more chemotherapeutic agents in the treatment of a human having a cancer selected from the group of: a solid tumour, renal cancer, breast cancer, lung cancer, prostate cancer, colon cancer and leukaemia.

Problems solved by technology

However, these correlative studies did not show a direct role for ribonucleotide reductase in cancer cell transformation and tumour progression, because like so many other enzyme activities found to be altered in cancer cells [e.g. Weber, 1983], the results could easily be explained by the increased cell proliferation and altered cell cycle regulation characteristics of transformed and malignant cell populations [Morgan and Kastan, 1997].

Method used

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  • Antisense oligonucleotides directed to ribonucleotide reductase r2 and uses thereof in the treament of cancer
  • Antisense oligonucleotides directed to ribonucleotide reductase r2 and uses thereof in the treament of cancer
  • Antisense oligonucleotides directed to ribonucleotide reductase r2 and uses thereof in the treament of cancer

Examples

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Effect test

example 1

In Vivo Testing of SEQ ID NO: 1 in Combination with Various Chemotherapeutics in Mouse Xenograft Models

[0193] 1.1 HT-29 human colon cancer cells (3×106 cells in 100 μl of PBS) were subcutaneously injected into the right flank of 6-7 weeks old female CD-1 nude mice. After the size of tumour reached an approximate volume of 50 mm3, 4 days post tumour cell injection, mitomycin C was administered by bolus infusion into the tail vein at days 4, 11 and 18 with a dose of 3.5 mg / kg / week. Antitumour effect of mitomycin C was further compared to that of SEQ ID NO:1 in combination with mitomycin C. SEQ ID NO:1 was administered by bolus infusion into the tail vein every day at 6 mg / kg and mitomycin C was administered intravenously at days 4, 11 and 18 with a dose of 3.5 mg / kg / week, one hour after the treatments with SEQ ID NO:1. Control animals received saline alone for the same period as SEQ ID NO:1. All treatments were stopped at day 22. A day after the last treatment, tumours were excised f...

example 2

In Vivo Testing of SEQ ID NO:1 Alone or in Combination with Various Chemotherapeutics in Drug-Resistant Tumours

[0207] 2.1 BxPC-3 human pancreatic carcinoma cells (3×106 cells in 100 μl of PBS) were subcutaneously injected into the right flank of 6-7 weeks old female CD-1 nude mice. BxPC-3 is a gemcitabine resistant call line. After the size of tumour reached an approximate volume of 100 mm3, 21 days post tumour cell injection, SEQ ID NO: 1 was administered by bolus infusion into the tail vein every other day at 10 mg / kg 17 times. Control animals received saline alone for the same period. Antitumour effect of SEQ ID NO: 1 was further compared to that of Gemcitabine. Gemcitabine was administered intravenously every three days at a dose of 100 mg / kg. Antitumour activities were estimated by the inhibition of tumour volume, which was measured with caliper. Each point represents mean tumour volume calculated from 10 animals per experimental group. As illustrated, SEQ ID NO: 1 treatments ...

example 3

In Vivo Testing of SEQ ID NO:1 Alone in Mouse Xenograft Models

[0216] 3.1 HT-29 human colon cancer cells (3×106 cells in 100 μl of PBS) were subcutaneously injected into the right flank of 6-7 week old CD-1 female nude mice. After the size of tumour reached an approximate volume of 100 mm3, 4 days post tumour cell injection, SEQ ID NO:1 was administered by bolus infusion into the tail vein every other day at 10 mg / kg. Control animals received saline alone for the same period. Treatments lasted for 14 days thereafter. Antitumour activities were estimated by the inhibition of tumour volume, which was measured with a caliper on four different occasions over the treatment period. Each point represents mean tumour volume calculated from 5 animals per experimental group. As illustrated, SEQ ID NO:1 treatment demonstrated statistically significant inhibitory effects (P=0.0001) on the growth of human colon adenocarcinoma (see FIG. 17A). [0217] Antitumour effects of SEQ ID NO:1 were shown to...

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Abstract

The present invention provides antisense oligonucleotides directed to a mammalian ribonucleotide reductase R2 gene and combinations of the antisense oligonucleotides with one or more chemotherapeutic agents for use in the treatment of cancer.

Description

FIELD OF THE INVENTION [0001] The present invention pertains to the field of cancer therapeutics and in particular to the use of antisense oligonucleotides alone or in combination with one or more chemotherapeutic drugs for the treatment of cancer. BACKGROUND [0002] Regulation of ribonucleotide reductase, and particularly the R2 component, is altered in malignant cells exposed to some tumour promoters and to the growth factor TGF-β [Amara, et al., 1994; Chen et al., 1993; Amara et al., 1995b; Hurta and Wright, 1995; Hurta et al., 1991]. Higher levels of enzyme activity have been observed in cultured malignant cells when compared to nonmalignant cells [Weber, 1983; Takeda and Weber, 1981; Wright et al., 1989a], and increased levels of R2 protein and R2 mRNA have been found in pre-malignant and malignant tissues as compared to normal control tissue samples [Saeki et al., 1995; Jensen et al., 1994]. However, these correlative studies did not show a direct role for ribonucleotide reduct...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K31/7072A61K31/7048A61K31/704A61K31/4745A61K31/573C07H21/02A61K31/19A61K38/00C12N15/113
CPCA61K31/19A61K31/4745A61K31/573A61K31/704C12N2310/315A61K31/7072A61K38/00C12N15/1137A61K31/7048A61P35/00A61P35/02
Inventor WRIGHT, JIM
Owner LORUS THERAPEUTICS
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