Effect of indomethacin plus ranitidine in advanced melanoma patients on high-dose interleukin-2

Mertens, Wilson C.; Bramwell, Vivien; Gwadry-Sridhar, Femida; Romano, Walter; Banerjee, D.; Lala, Peeyush K.

doi:10.1016/0140-6736(92)91474-m

Cited by 24 publications

(5 citation statements)

References 7 publications

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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 We show that aberrant over-expression of cyclooxygenase Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:(COX)-2, an inflammation-associated enzyme, occurring in 40-50% of breast cancer patients leads to tumor progression and metastasis due to multiple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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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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“…Studies with animal tumor models have dem onstrated promising results of immunothera py with IL-2 and LAK cells [7][8][9], However, clinical trials have shown that the use of IL-2 and LAK cells is only effective in the treat ment of some patients with metastatic renal cell carcinoma or with malignant melanoma [10][11][12], Therefore, one of our research goals is to search for the agents which modify IL-2-induced LAK cell activity in order to in crease the effectiveness of adoptive immuno therapy for cancer [13][14][15], Indomethacin, a cyclooxygenase inhibitor, is a documented immune modulator that upregulates immune function by suppressing the biosynthesis of the immunosuppressive agent, prostaglandin E2 (PGE2) [16][17][18][19], In combination with IL-2, indomethacin has been used in vitro to augment LAK cell activi ty generated from lymphoid cells [20][21][22][23][24] and in vivo in advanced melanoma patients [25], although it is more commonly used for the purpose of preventing a side effect of IL-2 administration, e.g. fever and chills [10][11][12],…”

Section: Introductionmentioning

confidence: 99%

Effects of Indomethacin on Lymphokine-Activated Killer Cell Activities in Cancer Patients

Chao¹,

Ting²,

Yeh³

et al. 1995

Tumor Biol

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Prostaglandin E₂ (PGE₂) is known to downregulate the generation of lymphokine-activated killer (LAK) cell activity. Indomethacin, an inhibitor of cyclooxygenase catalyzing the biosynthesis of PGE₂, has been shown to augment LAK cell activities generated from peripheral blood mononuclear cells of normal healthy individuals. This study was undertaken to examine whether or not this augmentation is also a common phenomenon in cancer patients. LAK cell activities generated in the presence and the absence of indomethacin were examined in 15 normal healthy individuals and in 83 cancer patients. Paired data analysis revealed that indomethacin exhibited a significant augmentation of LAK activity generated from healthy individuals. Indomethacin enhanced LAK activity in patients with no distant metastases (T_xN_xM₀); but depressed LAK activity in patients with distant metastases (T_xN_xM₁). In patients without distant metastases, indomethacin showed an upregulating effect on LAK activity in those with an early T stage (T_1-2N_xM₀), and no such effect was detected in those with a late T stage (T_3-4N_xM₀). Indomethacin also significantly enhanced LAK cell generation in cancer patients with an ECOG performance status of 1, but significantly inhibited LAK cell generation in patients with a performance status of 4. These results indicated that indomethacin inhibited generation of LAK cell activity in cancer patients with a poor performance status or with distant metastatic disease, who normally would be the subjects of adoptive immunotherapy. Further, PGE₂ production in cultured LAK cell medium was suppressed by indomethacin in all 20 cancer patients that were examined, suggesting that other yet to be identified factors or mechanisms may be responsible for the paradoxical effects of indomethacin on LAK cell activity.

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“…38 In fact, side-effects on normal tissues, could be investigated using lymphoid cancers in animals 42 and humans. 43 The use of such layer or 2-mercaptoethanol. J Cell Physiol 1981; 107: 283-293.…”

mentioning

confidence: 99%

Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells

et al. 1997

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Analysis of rat, pre-T cell 'Nb2 lymphoma' sublines, manicell lines 5.6 which can be used for investigating biochemical, festing different degrees of malignant progression, can indicate chromosomal and molecular genetic mechanisms underlying phenotypic changes potentially useful as therapeutic targets.the malignant progression of certain T cell cancers, includingIn this study, the prolactin (cytokine)-dependent Nb2-11 and loss of a dependency on growth factors (cytokines) 7-9 and autonomous Nb2-SFJCD1 sublines were compared for in vitro development of tissue invasiveness and metastatic ability.10 thiol growth requirements. Whereas Nb2-11 culture growth depended on 2-mercaptoethanol (2-ME; 33-100 M), Nb2-The system consists of a parental line of cultured rat pre-T SFJCD1 cells were 2-ME-independent. This difference stemmed lymphoma cells, designated 'Nb2 lymphoma', and a number and growth of the parent Nb2 lymphoma cell line are criti-2-ME enhanced cystine uptake to growth-sustaining levels.cally dependent on the polypeptide hormone, prolactin (PRL),Nb2-SFJCD1 cells did not require 2-ME due to intrinsic, 11-fold higher cystine uptake via the x − − − c cystine/glutamate transport acting as a growth factor (cytokine). 10 In contrast, the growth system. In absence of 2-ME, monosodium glutamate abrogated of Nb2 sublines, obtained by culturing the parent cells in lishment of the first Nb2 lymphoma cell cultures. 5 As reported by various groups, 2-ME can enhance the uptake of L-cystine by lymphoid cells.12-14 L-Cystine or its reduced form, L-cystIntroduction eine, is an essential amino acid for mammalian lymphocytes, and a number of malignant human and animal cell lines of Cancers typically become more aggressive with time and follymphoid origin, which lack the ability to synthesize the lowing ineffective therapy. This phenomenon, termed tumor amino acid. 15,16 Consequently, the growth of such cells is or malignant progression, is manifested by phenotypic procritically dependent on the levels of the amino acid in their perty changes of the cancers, including an increase in growth microenvironment. While lymphoid cells can readily take up rate; loss of a growth requirement for hormones and growth extracellular cysteine, they have, in general, a very low uptake factors; development of tissue invasiveness, metastatic ability capability for cystine, 16,17 which is the dominant form of the and drug resistance.1 At the cellular level, tumor progression amino acid in tissue culture medium or in the circulation, is typified by chromosomal alterations and gene mutations since cysteine is rapidly oxidized to cystine. 11,18 In vitro, the leading to tumor cell heterogeneity and outgrowth of more cyst(e)ine requirement of lymphoid cells can be accommovirulent, autonomous and therapy-resistant sublines (clonal dated by the presence in the medium of cystine at elevated evolution).2,3 Tumor progression poses a very serious problem concentrations or, alternatively, by the presence of a thiol to the clinical management of cancer.1-3...

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Effect of indomethacin plus ranitidine in advanced melanoma patients on high-dose interleukin-2

Cited by 24 publications

References 7 publications

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

EP4 as a Therapeutic Target for Aggressive Human Breast Cancer

Effects of Indomethacin on Lymphokine-Activated Killer Cell Activities in Cancer Patients

Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells

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