Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma

Morant, Rudolf; Bernhard, J.; Maibach, Rudolf; Borner, Markus; Fey, Martin F.; Thürlimann, Beat; Jacky, E; Trinkler, Felix; Bauer, Jean; Zulian, Gilbert; Hanselmann, Silvia; Hürny, Christoph; Hering, F.

doi:10.1023/a:1008332724977

Cited by 45 publications

(42 citation statements)

References 18 publications

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“…Its antiproliferative effect in androgenindependent CaP cell lines 31 gave rise to clinical expectations but its benefit in androgen-independent CaP patients was modest mainly due to its peripheral toxicity. [32][33][34] As targeted delivery cannot be based only on a simplified hypothesis that a cancer cell specific ligand will lead to preferable interaction and internalization of the drug in the cancer cell, other important factors should be taken into consideration, such as systemic targeting, tumor penetration, tumor heterogeneity. 43 For this reason, in this manuscript the focus was not only to enrich the repository of GnRH conjugates with new chemical entities which target GnRH-R positive cancer cells, but also to improve the therapeutic potential of gemcitabine, a very potent drug with poor pharmacokinetic properties.…”

Section: Discussionmentioning

confidence: 99%

“…29,30 Previous in vitro studies demonstrated that gemcitabine has exceptional antiproliferative effects in androgen-independent CaP cell lines 31 but modest clinical benefit when tested as monotherapy or combination therapy, mainly due to its severe peripheral side effects. [32][33][34] Many efforts aiming to enhance the therapeutic status of gemcitabine by chemical modifications have been reported. 30 These modifications have been focused on either improving gemcitabine's pharmacokinetics or reducing resistance induction.…”

Section: Introductionmentioning

confidence: 99%

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GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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“…Hejna et al assessed the regimen Docetaxel, Gemcitabine and granulocyte-colony stimulating factor in treatment of advanced non-small cell lung carcinoma and found this treatment to have significant activity [10]. In the treatment of CRMPC Morant et al showed that single agent gemcitabine had a significant beneficial impact on pain despite its limited efficacy in terms of PSA response [11]. However, there is only limited literature available on the anti-tumour efficacy and tolerance of DGP to treatment of CRMPC.…”

Section: Introductionmentioning

confidence: 99%

Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

Buch-Hansen

Bentzen

Hansen

et al. 2009

Cancer Chemother Pharmacol

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Purpose:We assessed the efficacy and toxicity of a fixed dose of docetaxel and prednisone, combined with escalating doses of gemcitabine (DGP). The primary endpoint was PSA response. Methods:Fifteen patients (pts) were enrolled in the phase I and 50 pts entered the phase II. Pts were given DGP, maximum of 8 courses, until progression or unacceptable toxicity. Docetaxel 75 mg/m 2 was administered intravenously day 1, gemcitabine was given day 1 and 8 in doses increasing from 600 to 1,000 mg/m 2 every third week. Pts had castrate refractory metastatic prostate cancer (CRMPC), adequate function of liver, kidney and bone marrow; ECOG performance status ≤2 and were chemotherapy-naïve. Results:Median age was 64 range (49-77). Twenty-one (42%) were PS 0, 26 (52%) were PS 1 and 3 (6%) were PS 2. The median pre-treatment PSA was 448 (12-4.580). No dose limiting toxicity was observed even with the highest dose level in the phase I part of the study. In the phase II part, PSA response was observed in 37(74%) pts. Twenty-four (48%) pts had measurable disease; 12 (50%) had partial remission, 5 (21%) had stable disease, 7 (29%) were not evaluable. Time to progression (TTP) was 7.9 months and overall survival (OS) was 13.9 months. Thirty-seven pts (74%) developed neutropenia, non-haematological toxicity was modest. Conclusions:The PSA response rate was promising and the toxicity of DGP was manageable; however OS was comparable to results of treatment with single agent docetaxel.

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“…Starting in 1991, the Swiss Group for Clinical Cancer Research (SAKK) conducted four consecutive phase II trials within the framework of a master protocol to evaluate carboplatin (Jungi et al, 1998), idarubicin (Schmid et al, 1997), gemcitabine (Morant et al, 2000) and vinorelbine (Morant et al, 2002b), in patients with HRPC. The goal of these studies was to find promising new drugs for further testing in phase III trials.…”

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confidence: 99%

Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

Morant¹,

Bernhard

Dietrich

et al. 2004

Br J Cancer

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The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda s ) at a dose of 1250 mg m À2 orally twice daily on days 1 -14 every 21 days. The inclusion criteria were PSA serum levels 43 Â upper limit of normal, a WHO performance status 0 -2, age o85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54 -85 years). A median of three cycles of capecitabine was administered (range 1 -8). PSA response was observed in three patients (12%, 95% CI 3 -31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9 -15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand -foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7 -41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg m À2 orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.

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Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma

Abstract: Gemcitabine in the dose and schedule indicated above has a significant beneficial impact on pain in patients with hormone-refractory prostatic carcinoma despite its limited activity in terms of PSA response and considerable, especially hematological, toxicity.

Cited by 45 publications

References 18 publications

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

Capecitabine in hormone-resistant metastatic prostatic carcinoma – a phase II trial

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