The future of antisense therapy: combination with anticancer treatments

Biroccio, Annamaria; Leonetti, Carlo; Zupi, Gabriella

doi:10.1038/sj.onc.1206812

Cited by 74 publications

(47 citation statements)

References 102 publications

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“…Tumor genes were rescued and sequenced. Genes expressed in sense orientation were considered candidate oncogenes, and those expressed in antisense orientation, which could potentially downregulate the expression of their counterpart in NIH3T3 cells (Biroccio et al, 2003), were considered candidate tumor suppressor genes. We performed two parallel studies using RNAs from either a mixture of four primary breast cancers or a mixture of three primary prostate cancers.…”

Section: Functional Screening Approach For the Identification Of Tumomentioning

confidence: 99%

UTRN on chromosome 6q24 is mutated in multiple tumors

Huang

Zhao

et al. 2007

Oncogene

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Section: Functional Screening Approach For the Identification Of Tumomentioning

confidence: 99%

UTRN on chromosome 6q24 is mutated in multiple tumors

Huang

Zhao

et al. 2007

Oncogene

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“…The possibility of impairing different molecular pathways that regulate tumor cell survival may be particularly advantageous, especially in the case of combinations free of side effects. Among the increasing number of target-specific drugs currently under investigation, antisense oligonucleotides (ODN) capable of interfering with tumor cell growth or apoptotic signaling as well as cancer cell invasiveness and metastatization, seem particularly promising for combination therapy in view of their lack of toxicity (1). Moreover, antisense strategies aimed at restoration of apoptotic signaling may be useful in overcoming tumor chemoresistance (2,3).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Efficacy of bcl-2 and c-myc Antisense Oligonucleotides in Combination with Cisplatin in Human Melanoma Xenografts: Relevance of the Administration Sequence

Zupi

Scarsella

Semple

et al. 2005

Clinical Cancer Research

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Purpose: bcl-2 and c-myc oncogenes are frequently overexpressed in different human tumors, including melanoma. Here, we evaluate the combined efficacy of two antisense oligonucleotides targeting bcl-2 mRNA (ODN bcl-2) and c-myc mRNA (ODN c-myc) in combination with cis-diammine dichloroplatinum (cisplatin, DDP) on three human melanoma lines (LM, NG, and M20).Experimental Design: Two different sequences were designed to treat tumor-bearing mice: in the first one, ODN bcl-2 at a dose of 0.2 mg/day Â Â Â Â Â 4, followed by DDP given i.p. at a dose of 3.3 mg/kg/day Â Â Â Â Â 3 and ODN c-myc i.v. at 0.5 mg/ day Â Â Â Â Â 7, whereas the other sequence consisted of ODN c-myc given as first agent followed by DDP and ODN bcl-2 at the same doses. Mice received three complete cycles of treatment in 1-week intervals.Results: The treatment sequence with ODN bcl-2/DDP/ ODN c-myc combination completely inhibited growth in NG tumor and induced a 35-day delay in LM tumor growth. In contrast, the M20 tumor growth was unaffected by the combination. A discrete amount of c-Myc and bcl-2 protein expression in both LM and NG tumors was detected, whereas no detectable levels of the two proteins were observed in M20 tumors. Compared with the other combination, the sequence ODN bcl-2/DDP/ODN c-myc produced the most effective results, producing a significant decrease in bcl-2 and c-Myc protein expression, which in turn significantly increased the survival of NG-and LMbearing mice, with 4 mice out of 11 and 1 out of 7 mice being cured, respectively. Finally, this combination increased the apoptotic rate and produced an antiangiogenetic effect.Conclusions: These results show that an antisense approach to the treatment of melanoma xenografts overexpressing either bcl-2 or c-myc oncogenes represents a successful strategy to improve the response to chemotherapy in melanoma, with particular attention to the treatment sequence.

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“…This may well account for the observed difference reported for antisense efficacy on small and large tumors 10 and may be part of the explanation as to why this agent has not demonstrated greater potency in clinical studies. This has led to the view that ASOs are quite likely to be more effective when used in combination with cytotoxic therapies, 20 and to address this, we explored the activity of ISIS 5132 in combination with the drugs most extensively used to treat ovarian cancer, carboplatin and taxol. When combined with either agentalone (Figs.…”

Section: Resultsmentioning

confidence: 99%

Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

et al. 2005

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In this study, we characterize the uptake and specificity of a firstgeneration Raf-1 antisense oligonucleotide (ASO) (ISIS 5132) and compare it with a second-generation ASO (ISIS 13650) and an RNA interference approach. All three approaches resulted in inhibition of both Raf-1 expression and cellular growth. Specificity of the Raf-1 ASOs was confirmed by comparison with ASOs targeted against another Raf isoform (B-Raf) as well as mismatch sequences. Cellular uptake studies with FAM-labelled ISIS 5132 revealed that whilst the majority of cells treated at a low-intermediate plating density were labelled within 3 hr, cells treated at high density demonstrated neither Raf-1 protein knockout nor significant growth inhibition, following similar treatment. This lack of response at high cell densities was associated with reduced pERK and Raf-1 inhibition. Cell cycle analysis revealed that whilst SKOV-3 cells both accumulated in the S-phase of the cell cycle and showed enhanced annexin V levels, following Raf-1 ASO treatment; these effects were also demonstrated with first-generation but not second-generation mismatch oligonucleotides. Bromodeoxyuridine incorporation analysis suggested that these effects may indeed be partly attributable to sequence nonspecific effects. Finally, the combination of ISIS 5132 with either carboplatin or taxol showed enhanced growth inhibition, supporting the view that such ASOs may have a more effective clinical role when used in combination with cytotoxic agents. ' 2005 Wiley-Liss, Inc.

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The future of antisense therapy: combination with anticancer treatments

Cited by 74 publications

References 102 publications

UTRN on chromosome 6q24 is mutated in multiple tumors

UTRN on chromosome 6q24 is mutated in multiple tumors

Antitumor Efficacy of bcl-2 and c-myc Antisense Oligonucleotides in Combination with Cisplatin in Human Melanoma Xenografts: Relevance of the Administration Sequence

Comparison of strategies targeting Raf-1 mRNA in ovarian cancer

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