Low Activity of 13-cis-Retinoic Acid Plus Interferon Alpha 2a in Advanced Renal Cell Carcinoma

Jaremtchuk, A.V; Aman, E.; Ponce, Walter; Zarbá, Juan José; Ferro, Alejandro; Álvarez, Ricardo H.; Vigo, Silvina A.

doi:10.1097/00000421-200204000-00004

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…The results of the current study confirm previously published experience of definite but low activity of IFN monotherapy and IFN‐CRA combination treatment in patients with MRCC15, 21–25 (IFN, 6%; IFN‐CRA, 19%). Although they were life‐threatening only rarely, systemic side effects led to the discontinuation of treatment in 22% of patients, and the addition of CRA increased the risk of side effects.…”

Section: Discussionsupporting

confidence: 91%

Interferon‐α‐2a with or without 13‐cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

Fosså

Mickisch

Mulder

et al. 2004

Cancer

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BACKGROUNDIn patients with metastatic renal cell carcinoma (MRCC), interferon‐α (IFN) monotherapy leads to response rates of 5–15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13‐cis retinoic acid (CRA).METHODSIn a randomized Phase II study, patients with measurable MRCC received either subcutaneous IFN (9 MU daily; Arm A) or the same daily subcutaneous dose of IFN plus oral CRA (1 mg/kg; Arm B). A central expert panel reviewed the X‐ray documentation of objective responses.RESULTSIn the 50 eligible patients from Arm A, the objective, expert‐reviewed response rate was 6% (95% confidence interval [95% CI], 1.3–16.6%; 2 complete responses [CRs] and 1 partial response [PR]). A 19% response rate (95% CI, 9.4–32.0%) was stated for 53 eligible patients from Arm B (2 CRs and 8 PRs). Only one of the four CRs claimed by the clinical investigator was confirmed by the central review committee. Conversely, the expert committee deemed that 3 of 12 investigator‐stated PRs were CRs. Constitutional toxicity (flu‐like symptoms) and/or side effects from skin, mucosa, or eyes led to discontinuation of treatment in 22% of nonprogressing patients, more often in Arm B than in Arm A.CONCLUSIONSThe results from this randomized Phase II study support expansion of the trial into a Phase III study to evaluate the effect of IFN‐CRA combination therapy on the survival of patients who undergo nephrectomy prior to IFN‐based immunotherapy. The considerable interobserver variability of response evaluation (individual investigator vs. expert panel) indicates the necessity of a central review of claimed responses in future Phase II studies involving patients with MRCC. Cancer 2004. © 2004 American Cancer Society.

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Section: Discussionsupporting

confidence: 91%

Interferon‐α‐2a with or without 13‐cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

Fosså

Mickisch

Mulder

et al. 2004

Cancer

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“…HDAC inhibition with 50 ng/mL treatment diminishes over the 24-hour period, with a 5-to 7-fold increase in acetylation over control by 16 hours, and there are minimal differences between TSA-treated and untreated samples by 24 hours. The 100 ng/mL TSA dose results in a consistent 10 controls, at all three time points tested. The presence or absence of ATRA did not affect the overall degree of hyperacetylation of histone H3.…”

Section: Resultsmentioning

confidence: 54%

“…RARs and retinoid X receptors interact with transcriptional coactivator and corepressor complexes that determine their activation state, with coactivator complexes possessing histone acetyltransferase activity and corepressor complexes possessing histone deacetylase (HDAC) activity (5,6). Pharmacologic doses of RA are currently being used to treat several types of cancer and have been used in combination with IFN in the treatment of RCC, in addition to head and neck and squamous cell carcinomas of the skin (7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model

Touma

Goldberg²,

Moench

et al. 2005

Clinical Cancer Research

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Purpose: Therapy for advanced renal cell carcinoma (RCC) is ineffective in the majority of patients.We have previously reported that retinoid-induced up-regulation of retinoic acid receptor h (RARh) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RARh 2 expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RARh 2 receptor expression, leading to increased growth inhibition in RCC cells. Experimental Design: Cell proliferation,Western blot, and reverse transcription-PCR analyses of two RA-resistant RCC cell lines, SK-RC-39 and SK-RC-45, were assessed in the presence of alltrans retinoic acid (ATRA), trichostatin A (TSA), or the combination of ATRA andTSA. Analysis of apoptosis was also done on SK-RC-39 cells treated with these combinations. Additionally, a xenograft tumor model (SK-RC-39) was used in this study to investigate the efficacy of a liposomeencapsulated, i.v. form of ATRA (ATRA-IV) plus TSA combination therapy. Results: Enhanced inhibition of the proliferation of RCC cell lines and of tumor growth in a xenograft model was observed with the combination of ATRA plus TSA. Reactivation of RARh 2 mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone or TSA in combination with ATRA. A partial G 0 -G 1 arrest and increased apoptosis were observed with SK-RC-39 cells on treatment with ATRA and TSA. Conclusions: The combination of ATRA and the histone deacetylase inhibitorTSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that ATRA and histone deacetylase inhibitor therapies should be explored for the treatment of advanced RCC.

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Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2

et al. 2005

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Low Activity of 13-cis-Retinoic Acid Plus Interferon Alpha 2a in Advanced Renal Cell Carcinoma

Cited by 6 publications

References 9 publications

Interferon‐α‐2a with or without 13‐cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

Interferon‐α‐2a with or without 13‐cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model

Apoptotic events induced by naturally occurring retinoids ATRA and 13-cis retinoic acid on human hepatoma cell lines Hep3B and HepG2

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