Incidence Rate of Injection-Site Granulomas Resulting from the Administration of Luteinizing Hormone-Releasing Hormone Analogues for the Treatment of Prostatic Cancer

Shiota, Masaki; Tokuda, Noriaki; Kanou, Takehiro; Yamasaki, Humio

doi:10.3349/ymj.2007.48.3.421

Cited by 19 publications

(35 citation statements)

References 5 publications

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“…Poor stability of GnRH analogs necessitates their subcutaneous administration (depot formulations) and leads to several side effects such as leukocytoblastic vasculitis (Turk et al, 2007) and injection site granulomas (Shiota et al, 2007). Most likely, GnRH analogs in clinical use achieve the desired pharmacological effects by action primarily on the pituitary and to a much lesser extent by direct antiproliferative effects on tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

Κάτσιλα

Balafas²,

Liapakis³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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Gonadotropin-releasing hormone (GnRH) receptor agonists have wide clinical applications including the treatment of prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive peptide [Des-Gly 10 ,Tyr 5 (OMe),D-Leu 6 ,Aze-NHEt 9 ]GnRH, analog 1, is presented herein and compared with leuprolide. Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using testosterone as a biomarker. Analog 1, an agonist of the GnRH receptor with a binding affinity in the nanomolar range, caused testosterone release in mice that was acutely dose-dependent, an effect blocked by the GnRH receptor antagonist cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of leuprolide, based on plasma and testis testosterone reduction and histopathological findings. Analog 1 also shared with leuprolide similar significant antiproliferative activity on androgen-dependent prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of cancer and endocrine disorders.

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Section: Discussionmentioning

confidence: 99%

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

Κάτσιλα

Balafas²,

Liapakis³

et al. 2011

The Journal of Pharmacology and Experimental Therapeutics

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“…Granulomas induced by luteinizing hormone-releasing hormone analogues have been reported in some patients for the treatment of prostatic cancers [51]. Histopathologically, epithelioid granulomatous inlammation with small vacuoles derived from the constituent ingredients of drug microcapsules has been observed [52].…”

Section: Drug-induced Granulomatous Reactionmentioning

confidence: 97%

Drug-Induced Cutaneous Toxicity

Yoshizawa¹,

Yuki²,

Tsubura³

2016

Toxicology - New Aspects to This Scientific Conundrum

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The skin is the largest organ in the body and is continually exposed to external stimuli, such as chemical and environmental substances. Cutaneous toxicity can be broadly classiied according to the mechanism of onset, namely: contact dermatitis, i.e., damage resulting from contact with a substance (irritant dermatitis, allergic contact dermatitis, chemical burns) photosensitivity, i.e., caused by combined efects of a substance and ultraviolet light (phototoxic dermatitis, photoallergic contact dermatitis) contact urticaria chemical-induced acne pigmentary disturbance drug rash hair disturbance nail disturbance or tumor-induced. This review outlines the function and structure of the skin, outlining characteristics of these types of cutaneous toxicity. In recent years, advances have been made in the development of pharmaceutical products targeting speciic molecules or genes and nanotechnology-based pharmaceutical products, raising concerns about the onset of toxicity by novel mechanisms involving new pharmaceutical products. Therefore, it is important to understand the basic toxicity-related changes described herein.

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“…In spite of extensive research in the field of hormonal therapy and development of various GnRH agonists over the past three decades, GnRH peptide analogs still suffer from poor pharmacokinetic properties. Depot formulations that are injected subcutaneously are also available; however, they can lead to several side effects such as leukocytoblastic vasculitis (Turk et al, 2007) and injection-site granulomas (Shiota et al, 2007). Subcutaneous implants have also been developed.…”

Section: Introductionmentioning

confidence: 99%

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

Varamini

Mansfeld

Giddam

et al. 2017

International Journal of Pharmaceutics

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Graphical abstractGonadotropin-releasing hormone (GnRH) is an endogenous peptide with a short biological half-life. Although GnRH analogs (eg. triptorelin) are developed with enhanced stability compared to the native peptide, they still suffer from poor biological stability and pharmacokinetic properties. Furthermore, they are only effective in the treatment of hormone-dependent reproductive cancers. In this study we applied lipidation and glycosylation along with D-amino acid substitution at position 6 (D-Trp 6 ) to improve the stability, permeability, and consequently the potency of the GnRH peptide and triptorelin. We showed that the conjugation of GnRH with a lipid moiety and carbohydrates made all modified constructs (1-8) more stable than the parent peptide against enzymatic degradation (5.5 to 6.5 times). Two of the lactose-modified glycolipopeptides, 3 and 6, showed 27 and 16 times higher membrane permeability than the parent GnRH, respectively. All analogs with D-Trp 6 -substitution (4-6) exerted GnRH receptor-mediated antiproliferative activity in prostate and ovarian GnRH-receptor positive cell lines. They were more potent than triptorelin in the hormone-independent prostate cancer cell line: DU145. Compound 6 (lactose-modified) was the most potent analog for stimulating the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) gonadotropins from rat pituitary cells in vitro. The same glycolipopeptide exhibited a higher efficacy and duration of action in stimulating the release of LH than triptorelin in a preclinical mouse model. The superior activity 2 of lipid-and carbohydrate-substituted triptorelin analog 6 made it a promising candidate for the development of new GnRH agonists to treat both hormone-dependent and hormone-refractory prostate cancer..LIST OF ABBREVIATIONS

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Incidence Rate of Injection-Site Granulomas Resulting from the Administration of Luteinizing Hormone-Releasing Hormone Analogues for the Treatment of Prostatic Cancer

Cited by 19 publications

References 5 publications

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

Evaluation of a Stable Gonadotropin-Releasing Hormone Analog in Mice for the Treatment of Endocrine Disorders and Prostate Cancer

Drug-Induced Cutaneous Toxicity

New gonadotropin-releasing hormone glycolipids with direct antiproliferative activity and gonadotropin-releasing potency

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