518A2 Melanoma Cells Are Protected by G3139 and Other Antineoplastic Agents Against the Cytotoxic Effects of DTIC

Benimetskaya, Luba; Miller, Paul S.; Stein, C. A.

doi:10.1089/oli.2005.15.206

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…Numerous laboratory studies appear to provide circumstantial evidence for this speculation, as it has been shown that some mechanisms of resistance are operational in mediating resistance to DTIC [18] . Benimetskaya et al [19] recently reported that treatment of 518A2 melanoma cells with agents such as Bcl-2 antisense, cisplatin or gemcitabine induced cytoprotection to DTIC. It is tempting to conclude that cytoprotection to DTIC is a stress response to chemical proapoptotic stress.…”

Section: Discussionmentioning

confidence: 99%

Orally Administered Rapamycin, Dacarbazine or Both for Treatment of Human Melanoma Evaluated in Severe Combined Immunodeficiency Mice

Thallinger¹,

Skorjanec²,

Soleiman³

et al. 2008

Pharmacology

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Objective: In this experimental study, the antineoplastic potential of orally administered rapamycin in human melanoma was evaluated and compared with dacarbazine (DTIC) as well as with the antineoplastic effect of the combination of both drugs. Methods: The substances were tested using 2 human melanoma cell lines, 518A2, which is highly susceptible to DTIC, and 607B, which is moderately susceptible. A human melanoma severe combined immunodeficiency mouse xenotransplantation model was used. After development of palpable tumors, mice received oral rapamycin or saline over 18 days. Additionally, from treatment day 4 to 8, mice were randomly chosen to receive either DTIC or saline treatment. Results: The oral rapamycin treatment (1.5, 7.5, 15 and 30 mg/kg body weight) had an antineoplastic effect, ranging from 35 to 78% tumor weight reduction compared with the saline group. In DTIC less sensitive 607B tumors, rapamycin treatment (15 and 30 mg/kg body weight) was superior to DTIC treatment (p < 0.05). DTIC monotreatment reduced tumor weight in 518A2 tumors by 85% on average, whereas in 607B xenografts, no significant tumor weight reduction was observed compared with the saline group (p > 0.05). The combination of rapamycin and DTIC was not superior to rapamycin monotreatment in any cell line. Conclusion: These data indicate that oral rapamycin exerts a relevant antineoplastic effect on human melanoma cells. This effect appeared to be more pronounced in DTIC less sensitive melanoma xenografts.

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Section: Discussionmentioning

confidence: 99%

Orally Administered Rapamycin, Dacarbazine or Both for Treatment of Human Melanoma Evaluated in Severe Combined Immunodeficiency Mice

Thallinger¹,

Skorjanec²,

Soleiman³

et al. 2008

Pharmacology

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Oligonucleotide–polyamine conjugates: Influence of length and position of 2′-attached polyamines on duplex stability and antisense effect

Winkler

Saadat

Díaz‐Gavilán

et al. 2009

European Journal of Medicinal Chemistry

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Comparison of D-G3139 and Its Enantiomer L-G3139 in Melanoma Cells Demonstrates Minimal In Vitro but Dramatic In Vivo Chiral Dependency

Lai

Brown²,

Voskresenskiy

et al. 2007

Molecular Therapy

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G3139 (Genasense), an 18mer phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the Bcl-2 messenger RNA (mRNA), downregulates Bcl-2 protein and mRNA expression in many cell lines. However, both the in vitro and in vivo mechanisms of action of G3139 are still uncertain. The isosequential L-deoxyribose enantiomer L-G3139, which does not downregulate Bcl-2 expression, was synthesized to study the role of the Bcl-2 protein in melanoma cells. Both D-G3139 and L-G3139 bind nonspecifically to basic fibroblast growth factor with approximately the same K(c), and cause highly effective inhibition of net formation in 518A2 melanoma cells on Matrigel. The uptakes of D-G3139 and L-G3139 in melanoma cells were also similar. However, unlike D-G3139, L-G3139 does not produce poly ADP-ribose polymerase-1 and procaspase-3 cleavage at 9.5 h after the initiation of the transfection, but can activate the intrinsic pathway of apoptosis at approximately 48 h. Furthermore, treatment of A375 melanoma human xenografts in severe combined immunodeficiency (SCID) mice demonstrates that tumor growth is not inhibited by L-G3139, whereas D-G3139 significantly inhibits the rate of tumor growth. Furthermore, the immunostimulatory properties of L-G3139 appear to be nil, which differs dramatically from those of D-G3139. In conclusion, profound differences exist between D-G3139 and L-G3139 in vivo despite their similarities in vitro.

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518A2 Melanoma Cells Are Protected by G3139 and Other Antineoplastic Agents Against the Cytotoxic Effects of DTIC

Cited by 4 publications

References 21 publications

Orally Administered Rapamycin, Dacarbazine or Both for Treatment of Human Melanoma Evaluated in Severe Combined Immunodeficiency Mice

Orally Administered Rapamycin, Dacarbazine or Both for Treatment of Human Melanoma Evaluated in Severe Combined Immunodeficiency Mice

Oligonucleotide–polyamine conjugates: Influence of length and position of 2′-attached polyamines on duplex stability and antisense effect

Comparison of D-G3139 and Its Enantiomer L-G3139 in Melanoma Cells Demonstrates Minimal In Vitro but Dramatic In Vivo Chiral Dependency

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