Sustained Oral Indomethacin and Ranitidine with Intermittent Continuous Infusion Interleukin-2 in Advanced Renal Cell Carcinoma

Mertens, Wilson C.; Bramwell, Vivien; Banerjee, D.; Gwadry-Sridhar, Femida; Al-Mutter, Nahla; Parhar, Ranjit S.; Lala, Peeyush K.

doi:10.1089/cbr.1993.8.229

Cited by 13 publications

(4 citation statements)

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“…Thus, it is possible that our second round of IL-2 did not induce iNOS in the pleural vessels, which consequently remained resistant to leakage. The so called 'tolerance' to IL-2 toxicity after the initial round reported by our laboratory in the human (Mertens et al, 1993) and a milder fall in blood pressure after the second course of IL-2 reported by another laboratory (Hibbs et al, 1992) might be similarly explained.…”

Section: Discussionsupporting

confidence: 54%

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Orucevic

Lala

1996

Br J Cancer

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Summary We tested whether NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, can prevent interleukin 2 (IL-2)-induced capillary leakage in tumour-bearing mice without compromising the therapeutic benefits of IL-2. C3H/HeJ female mice transplanted s.c. with 2.5 x 105 C3-L5 mammary carcinoma cells were treated with: nothing, IL-2 (ten injections of 15 000 Cetus units i.p. every 8 h), L-NAME (0.1, 0.5, or 1 mg ml-1 drinking water), IL-2+L-NAME (0.1 or 0.5 or 1 mg ml-' drinking water).Therapies were given in one round (IL-2, days 10-13; L-NAME, days 9-13) or in two rounds (IL-2, days 10-13 and 20-23; L-NAME, days 9-13 and days 19-23) after tumour transplantation. Capillary leakage was measured from the water contents of the pleural cavities, lungs, spleen and kidneys. Effects of the therapies on the primary tumour size and the number of spontaneous lung metastases were also recorded. NO production was measured as the nitrite+nitrate levels in the serum and in the pleural effusion. After the first round of therapies, addition of L-NAME significantly reduced IL-2-induced pulmonary oedema and water retention in the spleen in a dose-dependent manner. It also significantly reduced the IL-2-induced rise in NO levels in the serum and pleural fluid, but did not affect IL-2-induced pleural effusion or water retention in the kidney. At later stages of tumour growth (day 23), tumours themselves induced significant fluid retention in the lungs and the kidney, which was not aggravated further with the second round of IL-2 therapy. At this time, L-NAME therapy alone ameliorated tumour-induced pulmonary oedema. During both rounds of therapy different doses of L-NAME alone caused a reduction of primary tumour growth as well as spontaneous lung metastases, which improved further with the addition of IL-2. The combination therapy was at least as effective as IL-2 therapy. In summary, L-NAME had anti-tumour effects in vivo, reduced the severity of IL-2-induced capillary leakage in some organs and did not compromise anti-tumour efficacy of IL-2 therapy. Thus, L-NAME could be a valuable adjunct to IL-2-based cancer therapy.Keywords: capillary leak syndrome; interleukin 2 cancer immunotherapy; mammary adenocarcinoma; nitric oxide; NG-nitro-L-arginine methyl ester Interleukin 2 (IL-2) therapy, alone or in combination with ex vivo-generated lymphokine-activated killer (LAK) cells, can cause tumour regression in mice (Rosenberg et al., 1985;Ettinghausen et al., 1988) and in man (Rosenberg, 1989;Fisher et al., 1988; Dutcher et al., 1989;Parkinson et al., 1990). Widespread clinical use of IL-2 has been limited by the low rate of complete remission and by severe toxicity Siegel and Puri, 1991). Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991). It has been observed in humans (Siegel and Puri, 1991; Margolin et al., 1989;Rosenberg et al., 1987) al., 1985) and tumour necrosis factor (TNF)-ca...

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Section: Discussionsupporting

confidence: 54%

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Orucevic

Lala

1996

Br J Cancer

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“…It was also effective in curing metastatic human melanomas grown in nude mice, which were NK cell competent [37]. Encouraged with these results, we tested this protocol in a singlecenter phase 2 human trial in advanced kidney cancer and melanoma patients with promising results [38][39][40][41][42]. However, high-dose systemic IL2 therapy soon became unpopular due to IL-2 mediated capillary leak syndrome (CLS), a major side effect leading to rapid fluid accumulation in tissues and serous cavities.…”

Section: Prostaglandin-inhibitors In Cancer Immunotherapy--a Historicmentioning

confidence: 99%

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Majumder¹,

Nandi²,

Omar³

et al. 2018

Preprint

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G protein-coupled receptors (GPCRs, also called seven-transmembrane or heptahelical receptors) are a superfamily of cell surface receptor proteins that bind to many extracellular ligands and transmit signals to an intracellular guanine nucleotide-binding protein (G protein). When a ligand binds, the receptor activates the attached G-protein by causing the exchange of Guanosine-5'-triphosphate (GTP) for guanosine diphosphate (GDP). They play a major role in many physiological functions as well as in the pathology of many diseases including cancer progression and metastasis. Only a few GPCR members have been exploited as targets for developing drugs with therapeutic benefit in cancer. Present review deals with the Prostaglandin E receptor EP4, a member of the EP family of GPCR, as a promising newer therapeutic target for treating breast cancer. We show that aberrant over-expression of cyclooxygenase Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:(COX)-2, an inflammation-associated enzyme, occurring in 40-50% of breast cancer patients leads to tumor progression and metastasis due to multiple cellular events resulting from an increased prostaglandin (PG) E2 production in the tumor milieu. They include inactivation of host anti-tumor immune (NK and T) cells, increased immuno-suppressor function of tumor-associated macrophages, promotion of tumor cell migration, invasiveness and tumor-associated angiogenesis (due to upregulation of VEGF-A), lymphangiogenesis (due to upregulation of VEGF-C/D) and a stimulation of stem-like cell (SLC) phenotype in cancer cells. All these events were primarily mediated by activation of the PGE receptor EP4 on tumor or host cells. We show that selective EP4 antagonists (EP4A) could mitigate all these events tested with cells in vitro as well as in vivo in syngeneic COX-2 expressing mammary cancer bearing mice or immune-deficient mice bearing COX-2 over-expressing human breast cancer xenografts. We suggest that EP4A can avoid thrombo-embolic side effects of long term use of COX-2 inhibitors by sparing cardio-protective roles of PGI2 via IP receptor activation or PGE2 via EP3 receptor activation. Furthermore, we identified two COX-2/EP4 induced oncogenic and SLC-stimulating microRNAs -miR526b and miR655, one of which (miR655) appears to be a potential blood biomarker in breast cancer patients, for monitoring SLC-ablative therapies such as with EP4A. We suggest that EP4A will likely produce the highest benefit in aggressive breast cancers such as COX-2 expressing triple-negative breast cancers, when combined with other newer agents such as PD-1 or PD-L1 inhibitors.

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“…This combination therapy was also beneficial in murine ascites tumors (Lala et al, 1990b) and was effective in curing experimental metastases of human melanomas grown in nude mice (Lala et al, 1990a). Subsequently, this combination therapy was shown to be promising in a phase 2 human trial of advanced melanomas (Mertens et al, 1993a) and renal cell carcinomas (Mertens et al, 1993b). Interestingly, some melanoma patients exhibited objective (complete and partial) responses to indo therapy alone (Mertens et al, 1992), indicating that PGE production in the host promoted tumor progression.…”

Section: Wiley-liss Incmentioning

confidence: 99%

Effects of chronic indomethacin therapy on the development and progression of spontaneous mammary tumors in C3H/HEJ mice

1997

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Sustained Oral Indomethacin and Ranitidine with Intermittent Continuous Infusion Interleukin-2 in Advanced Renal Cell Carcinoma

Cited by 13 publications

References 5 publications

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Effects of chronic indomethacin therapy on the development and progression of spontaneous mammary tumors in C3H/HEJ mice

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