GTI-2501, an antisense agent targeting R1, the large subunit of human ribonucleotide reductase, shows potent anti-tumor activity against a variety of tumors

Abstract

GTI-2501 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of R1, the large subunit of ribonucleotide reductase (RNR). In vitro studies, have demonstrated that GTI-2501 decreases mRNA and protein levels of R1 in a sequence-specific and dosedependent manner. Furthermore, GTI-2501 inhibits the growth of human lung, liver, ovary, brain, melanoma, breast and pancreatic tumor cells in colony forming assays. In vivo studies have shown that GTI-2501 significantly inhibits growth of human colon, pancreas, lung, breast, renal, ovarian, melanoma, brain glioblastoma-astrocytoma, and prostatic tumors in CD-1 nude, Balb/c nude and/or SCID mice. GTI-2501 treatment caused total regression of human breast and renal tumor xenografts in mice. These effects are not observed with a scrambled control oligonucleotide containing the same base content but not complementary to R1. GTI-2501 specifically inhibits metastasis of human melanoma cells to the lungs in CD-1 athymic nude mice and prolongs the survival of mice bearing human lymphoma. Taken together these results suggest that an antisense mechanism of action is responsible for growth inhibition in vitro and in vivo and that GTI-2501 can act as a selective and specific anti-tumor agent.

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells

“…As shown in antisense DNA oligo targeting RRM1, was also able to inhibit tumor growth in vitro and in vivo. 27 It however should be noted that RRM1-specific siRNA is only effective in tumors that overexpress RRM1 (Fig. 2E), but not in gemcitabine-sensitive parent TC-1 tumors that do not overexpress RRM1 (Fig.…”

Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells

“…It has been shown that higher inherent levels of RRM2 expression is associated with resistance to a variety of anticancer agents, including gemcitabine, hydroxyurea, 2,2-difluorodeoxycytidine, and 5-FU [16,19,20]. Recently, several studies reported that the inhibition of endogenous RRM2 using phosphorothioate antisense oligonucleotides or siRNA decreases malignant cell proliferation, and enhances chemosensitivity [21,22].…”

Capecitabine in Combination with Novel Targeted Agents in the Management of Metastatic Breast Cancer: Underlying Rationale and Results of Clinical Trials

“…GTI-2040 is a 20-base phosphorothioate oligonucleotide that is complementary to a coding region in the mRNA of the R2 small subunit component of human ribonucleotide reductase [81]. Preclinical studies have demonstrated that GTI-2040 inhibits the growth of a variety of cancer cell lines and tumors in breast cancer models; it also has been shown to reduce metastasis of melanoma to the lungs [81].…”