GTI-2040, an antisense agent targeting the small subunit component (R2) of human ribonucleotide reductase, shows potent antitumor activity against a variety of tumors.

GTI-2040 is a 20-mer oligonucleotide that is complementary to a coding region in the mRNA of the R2 small subunit component of human ribonucleotide reductase. In vitro studies using a number of human tumor cell lines have demonstrated that GTI-2040 decreases mRNA and protein levels of R2 in a sequence- and target-specific manner. In vivo studies have shown that GTI-2040 significantly inhibits growth of human colon tumors (adenocarcinoma), pancreatic tumors (adenocarcinoma), liver tumors, lung tumors, breast tumors (adenocarcinoma), renal tumors, ovarian tumors (adenocarcinoma), melanoma, brain glioblastoma-astrocytoma, prostatic tumors, and cervical tumors in nude and/or severe combined immunodeficient mice. Antitumor effects were not observed with an oligonucleotide containing four mismatches to the R2 sequence or with a scrambled sequence containing the same base content but not complementary to R2. This suggests that an antisense mechanism is responsible for the in vivo observations. In addition to tumor growth assays, GTI-2040 was tested in a murine model of human lymphoma. Treatment of severe combined immunodeficient mice bearing Burkitt's lymphoma with GTI-2040, but not control oligonucleotides, greatly extended the survival of mice, and survival extended well beyond the treatment period. Finally, GTI-2040 specifically inhibits metastasis of human melanoma cells to the lungs in nude mice. Taken together, the results of these studies indicate that GTI-2040 can act as a selective and specific anticancer agent against a broad range of human tumors.

Comparison of DR5 and Fas expression levels relative to the chemosensitivity of acute lymphoblastic leukemia cell lines.

The relationship between p53 gene status and the expression of DR5 and Fas was evaluated as a function of sensitivity of 11 acute lymphoblastic leukemia cell lines to adriamycin, etoposide, vincristine, methotrexate and dexamethasone. There was up to a 37-fold increase in expression of DR5 following treatment with ADR or VP-16 only in cells with wt p53. A direct correlation was observed between enhanced DR5 expression and sensitivity to ADR and VP-16. There was no induction of DR5 following treatment with VCR, MTX or DEX. There was up to a 51-fold increase in the median level of expression of Fas following treatment with ADR and VP-16, and unlike DR5 this occurred in cells with either wild-type or mutant p53. Nevertheless, a direct correlation was observed between Fas expression and drug-sensitivity. Conversely, there was only a two-fold increase in expression of Fas after exposure to VCR, MTX and DEX. These findings suggest that DR5 mediates sensitivity to ADR and VP-16 in a p53-dependent manner, whereas, Fas appears to mediate sensitivity to these two drugs independent of p53 status. DR5 and Fas do not appear to play a major role as determinants of chemosensitivity to VCR, MTX and DEX.