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Problems with glucocorticoid use in solid tumors

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Cancer Biol Ther. 2007 Feb;6(2):278-87. Epub 2007 Feb 27.
Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors.

Zhang C, Wenger T, Mattern J, Ilea S, Frey C, Gutwein P, Altevogt P, Bodenmüller W, Gassler N, Schnabel PA, Dienemann H, Marmé A, Hohenfellner M, Haferkamp A, Pfitzenmaier J, Gröne HJ, Kolb A, Büchler P, Büchler M, Friess H, Rittgen W, Edler L, Debatin KM, Krammer PH, Rutz HP, Herr I.
Research Group Molecular OncoSurgery, University of Heidelberg, Im Neuenheimer Feld 365, Heidelberg 69120, Germany.
BACKGROUND: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy-resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. MATERIAL AND METHODS: We performed an overall statistical analysis of our new and recent data with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. RESULTS: New in vivo results demonstrate glucocorticoid-induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid-induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid-derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti-emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti-emetic agents did not counteract anticancer treatment and may be sufficient to replace glucocorticoids in cotreatment of carcinoma patients. CONCLUSION: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC-induced cell-type specific pro- and anti-apoptotic signalling.

PMID: 17224649 [PubMed - indexed for MEDLINE]

10 page PDF of full text: http://www.landesbioscience.com/jour.../article/3652/

Excerpts:

GCs blocked the lethal signal delivered by a variety of clinically used cytotoxic drugs even if they were given several hours after induction of apoptosis.
Moreover, resistance induced by a single treatment with GCs lasted for up to 10 days before it started to decline, and resistance was noted at peak plasma concentrations found in patients and below. In contrast, alternative nonsteroidal antiemetic medicaments usesd in cancer therapy, such as a NK1 and a 5‑HT3 receptor antagonists, did not induce resistance.

Statistical evaluation of new and our recent data demonstrates that DEX‑induced resistance in solid tumors is the rule, not the exception.

we xenografted a human prostate cancer cell line to nude mice and measured tumor growth during a period of 15 days in untreated mice or upon treatment with paclitaxel, DEX, or paclitaxel and DEX together (Fig. 1). While paclitaxel alone resulted in a strong growth retardation, comedication of DEX induced therapy resistance, since the paclitaxel treated cells grew as fast as untreated control tumors. These results are similar to our recent in vivo studies using xenografted tumors of ovary, pancreas, colon and lung as well as 67 established cell lines and 85 freshly resected surgical specimen treated with various anticancer drugs in the presence or absence of GCs. Comedication of GCs induced therapy resistance, as evident from inhibited apoptosis and enhanced viability in 94% of the established cell lines, 85% of the primary cells and in all of a total of five examined tumor xenografts

To demonstrate that GCs counteract the effect of various cytotoxic agents, we treated P5 cells with several clinically used anticancer agents (Fig. 4B). DEX counteracted the effect of cisplatin, etoposide, cytarabine, gemcitabine, methotrexate, 5‑fluorouracil, paclitaxel and ionizing radiation as measured by analyzing apoptosis and viability. Thus, induction of resistance is common for several GCs and different cytotoxic treatments.

we report here, that (I) DEX‑induced therapy resistance is common for several cytotoxic treatments including cisplatin, etoposide, g‑irradiation, gemcitabine, methotrexate, 5‑fluorouracil, cytarabine and paclitaxel; (II) Resistance is due to inhibition of apoptosis, promotion of viability and cell cycle progression (III) Resistance lasts long but is reversible after removal of DEX; (IV) induction of resistance is common for several GC‑derivatives including DEX, betamethasone, hydrocortisone and prednisone; (V) nonsteroidal anti‑emetic agents used in cancer therapy such as serotonin‑receptor or NK1 receptor antagonists do not induce resistance. In addition, our data show that DEX‑mediated resistance occurs over a wide range of DEX concentrations resembling peak plasma levels found in patients,14 down to relatively low concentrations. Since lower concentrations occur in patients at later times after DEX administration, as plasma levels decline, this point leads to more concerns about safety and the question whether the level of naturally occurring GCs may interfere with cancer therapy.

Our findings suggest that GCs are highly suspicious to induce therapy resistance of solid tumors also in clinical settings and there are indeed several hints demonstrating an negative effect of corticosteroids on tumor growth in patients.6

In conclusion, GC‑cotreatment switches the balance between several interacting signaling pathways to death in lymphoid cells but to survival in cells derived from tissue or a solid tumor.

Most importantly, when applying these findings to the clinical situation, the protection of normal tissue by GCs may be of benefit for patients, but the protection of cells of a solid tumor may minimize the effect of cytotoxic therapy. Thus, our data suggest to replace GCs in prevention of cancer therapy‑induced emesis by nonsteroidal anti‑emetic agents, which do not induce therapy resistance.

Cancer Biol Ther. 2007 Sep;6(9):1345-54. Epub 2007 Jul 19.
Cell cycle arrest by glucocorticoids may protect normal tissue and solid tumors from cancer therapy.

Mattern J, Büchler MW, Herr I.
Molecular OncoSurgery, Department of Surgery, University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Glucocorticoids have been widely used as cotreatment for patients with cancer due to potent pro-apoptotic properties in lymphoid cells, reduction of nausea and diminishing acute toxicity on normal tissue. There are now data from preclinical and, to some extent, clinical studies, demonstrating that these medicaments are highly suspicious to induce therapy resistance in the majority of malignant solid tumors-irrespective of tumor origin and the nature of specific anticancer drugs or irradiation used for treatment. Despite these huge amounts of data, the underlying mechanisms of cell type-specific signaling by these steroid hormones are just beginning to be described. This review summarizes our present understanding of a relationship between glucocorticoid-induced reversible cell cycle arrest and therapy resistance in solid tumors. We give a summary of our current knowledge of decreased proliferation rates in response to glucocorticoid pre and combination treatment which are suspicious to be involved not only in protection of normal tissues, but also in protection of solid tumors from cytotoxic effects of anticancer agents. The inhibition of cell cycle progression by pretreatment with GCs may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with GCs.

PMID: 18087223 [PubMed - indexed for MEDLINE]

PDF of full text available:
http://www.landesbioscience.com/jour.../article/4765/

excerpts:

GCs strongly induce apoptosis in cells of the haematological lineage. This makes these compounds of tremendous value in the treatment of leukemias, lymphomas, and multiple myeloma.34 In contrast, cells of epithelial origin, such as mammary gland, ovarian follicular cells and hepatocytes as well as the majority of human solid malignant tumor cells are protected by GCs against various stimuli for apoptosis. Tumors involved have been found to be derived from bladder, brain, breast, cervix, colon, liver, lung, kidney, ovary, pancreas, prostate, rectum and testis and also gliomas, melanomas and osteosarcomas are rendered therapy resistant by GCscortisone treatment has also been found to favor an increased metastatic spread in patients with breast carcinoma,108,110 lung carcinoma109 and renal carcinoma (compare also Table 2).6,35 These GC‑induced protective effects may become clinically relevant.

Agosin et al.102 and Molomut et al.103 have reported an increase in the incidence of metastases in cortisone‑treated tumor‑bearing mice. These observation could be confirmed by many authors (Table 7).104‑106 However, .111 Recently, Sorensen et al.112 compared in a large population‑based follow‑up study among 59.043 individuals who received prescriptions for GCs, the observed and expected number of cases of skin cancer and non-Hodgkin lymphoma. They found an elevated risk for squamous cell carcinomas and basal cell carcinomas of the skin and also for non-Hodgkin lymphoma in patients who received prescriptions for GCs. These results further indicate that immunosuppression by GCs may be a risk for these malignancies.

Appl Immunohistochem Mol Morphol.


2009 Oct 28. [Epub ahead of print]
Estrogen Receptor, Progesterone Receptor, and Glucocorticoid Receptor Expression in Normal Breast Tissue, Breast In Situ Carcinoma, and Invasive Breast Cancer.

Buxant F, Engohan-Aloghe C, Noël JC.
*Gynecology daggerPathology, Erasme Hospital, Free University of Brussels (ULB), Belgium.
Glucocorticoids (GCs) are used in cancer treatment to induce programmed cell death in transformed cells of the hematopoietic system and to lessen side effects. Moreover, GCs have been described not only as inhibitors of some chemotherapy or radiation-induced apoptosis, but also as inhibitors of cancer progression by down-regulation or up-regulation of different gene expressions. Recently, it has been suggested that GCs can attenuate estrogen responses through induction of expression and activity of the sulfotransferase. The presence or absence of glucocorticoid receptor (GR) in normal and abnormal breast tissue is thus interesting, and the aim of this study was to analyze the expression of GR during the progression of breast tissue. We tested by immunohistochemistry the expression status of estrogen receptor (ER), progesterone receptor (PR), and GR in normal breast parenchyma (n=49), ductal intraepithelial neoplasia (DIN) 1a (n=9), DIN 1b-1c (n=15), DIN 2-3 (n=21), and invasive breast carcinoma (n=39). The evaluation of GR expression was made by using the Allred score. All the normal parenchyma, DIN 1a, DIN 1b, and DIN 1c were ER-positive (ER) and PR-positive (PR). Seventeen of 21 DIN 2-3 and 30 of 39 invasive carcinomas were ER/PR. The other samples were ER-negative (ER) and PR-negative (PR). Moreover, all the ER/PR samples were GR-negative. Interestingly, we found a significant correlation between the histologic grade and the GR-negative tumors, and a percentage of positive patients presented with nuclear immunoreaction to GR, which decreases significantly with tumor histologic grade. Understanding the role of GCs in breast carcinoma is thus essential before continuing the widespread use of GCs combined with antineoplastic drugs or agents in the clinical management of women with breast cancer.

PMID: 19875955 [PubMed - as supplied by publisher]