Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals

Abstract

The effects of hybrid cytotoxic LH-RH analogs, produced by linking anthraquinone or methotrexate to carrier LH-RH agonist [D-Lys6]LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate adenocarcinoma. The two cytotoxic LH-RH analogs T-98 [(D-Lys6)LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)], and AJ-04 [(D-Lys6)LH-RH linked to methotrexate (MTX)], carrier [D-Lys6]LH-RH, or the free cytotoxic compounds MTX and G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic LH-RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ-04, T-98, [D-Lys6]LH-RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH-RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH-RH analogs to tumors such as prostate cancer, which have receptors for LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy.

Expression of Receptors for Luteinizing Hormone-Releasing Hormone (LH-RH) in Prostate Cancers following Therapy with LH-RH Agonists

“…They exploit the presence of LH-RH receptors on the plasma membranes of various tumors and, through internalization, introduce the cytotoxic molecule. Several compounds have been developed and have shown significant antitumor effect (22). A targeted cytotoxic analog of LH-RH containing doxorubicin conjugated to [D-Lys] (6) LH-RH is now available and has been used clinically in women with gynecologic cancers expressing LH-RH receptors (23).…”

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

“…In an early in vivo study, rats bearing Dunning R-3327-H prostate adenocarcinomas were treated with prototypes of hybrid cytotoxic LHRH analogs containing anthraquinone or methotrexate (56). Large doses of these early cytotoxic analogs had moderate antitumor effects and caused a slightly greater tumor growth inhibition than the carrier peptide alone.…”

“…Large doses of these early cytotoxic analogs had moderate antitumor effects and caused a slightly greater tumor growth inhibition than the carrier peptide alone. Free anthraquinone or methotrexate given in equimolar doses were ineffective (56). Various cytotoxic LHRH analogs were also shown to inhibit the growth of estrogen-dependent and -independent MXT mouse mammary carcinoma in vivo (57).…”

“…Various cytotoxic LHRH analogs were also shown to inhibit the growth of estrogen-dependent and -independent MXT mouse mammary carcinoma in vivo (57). Because relatively large doses were used, it is likely that earlier cytotoxic LHRH analogs inhibited tumor growth by a combined hormonal and cytotoxic action (56,57).…”

Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone

“…Previously, various analogs of LH-RH containing antineoplastic radicals such as cisplatin, D-melphalan, anthraquinone derivatives, and methotrexate were designed, synthesized, and tested in our laboratory (1,15,16). Recently, we developed a series of highly active derivatives of doxorubicin (DOX) (17).…”