Combination of long-acting microcapsules of the D-tryptophan-6 analog of luteinizing hormone-releasing hormone with chemotherapy: investigation in the rat prostate cancer model.

Abstract

The effect of combining hormonal treatment consisting of long-acting microcapsules of the agonist [D-Trp6]LH-RH (the D-tryptophan-6 analog of luteinizing hormone-releasing hormone) with the chemotherapeutic agent cyclophosphamide was investigated in the Dunning R-3327H rat prostate cancer model. Microcapsules of LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 pg/day were injected intramuscularly once a month. Cyclophosphamide (Cytoxan) (5 mg/kg of body weight) was injected intraperitoneally twice a week.When the therapy was started 90 days after tumor transplantation-at the time that the cancers were well developed-and was continued for 2 months, tumor volume was significantly reduced by the microcapsules or Cytoxan given alone. The combination of these two agents similarly inhibited tumor growth but did not show a synergistic effect. In another study, the treatment was started 2 months after transplantation, when the developing tumors measured 60-70 mm3. (1,19,20), but hormone-independent cells originally present in the tumor, by a clonal selection process, eventually repopulate the tumor. As the prostate cancer progresses to a hormone-independent state, this produces a relapse to androgen-ablation therapy (1,19,20). The histological and biochemical similarities of the Dunning R-3327H prostate tumor to human prostate adenocarcinoma have made this tumor an acceptable model for the study of human prostate cancer. From 70% to 90%o of the cells of this tumor appear to be dependent on androgen for maximal growth stimulation (1,19). Rats bearing this tumor respond for a long period of time to surgical castration by tumor involution. However, after this initial response to castration, the tumor relapses and growth is reinitiated (1). Thus, this tumor was chosen since it mimics many of the properties of human prostate carcinoma.Antineoplastic agents have the established ability to kill tumor cells (1,(18)(19)(20)(21)(22)(23). Cyclophosphamide (Cytoxan) is one of the most commonly used agents for chemotherapy of prostate carcinoma and has had the most extensive trials (21-23). It is possible that the use of a combination of chemotherapeutic and hormonal methods would prevent or delay a condition whereby hormone-insensitive cells present in the originally endocrine-dependent tumor subsequently become the predominant component (1,18,19,22,23 tSchally,

Early versus late hormonal therapy for prostate cancer

“…Survival days of rats castrated on days 200 and 250 were similar to average survivals of intact, untreated control rats inoculated with the same tumor (350 days). A similar effect resulting from androgen ablation was observed with an LH-RH agonist [3]. In the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model, early castration or treatment with an antiandrogen, flutamide, also significantly reduced tumor growth and improved tumor-free survival [4][5][6].…”

Investigation of the Combination of the Agonist D-Trp-6-LH-RH and the Antiandrogen Flutamide in the Treatment of Dunning R-3327H Prostate Cancer Model

“…Tumors and various organs were removed, cleaned, carefully weighed, and then quickly frozen on dry ice. Serum levels of testosterone, prolactin, and LH were measured using radioimmunoassays as described previously [36,38,43]. All data are expressed as mean SE.…”

“…All data are expressed as mean SE. Statistical analyses were performed using a computer-assisted program as previously described [36,43].…”

“…Ongoing therapeutic trials with microcapsules of D-Trp-6-LH-RH in patients with prostate carcinoma, breast and ovarian cancer, endometriosis, and precocious puberty attest to their high efficacy [36,41,42]. In another recent study we showed that combined administration of the chemotherapeutic agent cyclophosphamide together with microcapsules of D-Trp-6-LH-RH inhibits both androgen-dependent and -independent cell clones and further improves the therapeutic response [43].…”

Adjuvant Therapy in Prostate Cancer: Patient Identification and Treatment Options

“…Isaacs [75], using serially transplantable androgen-sensitive Dunning R3327H rat prostate adenocarcinoma as a model, found that castration had no effect when performed 250 days after tumour inoculation, but did extend survival (350 -470 days) if implemented at the same time as tumour inoculation. In another study [76], the combination of hormonal therapy (a long-acting LHRH microcapsule) with chemotherapy (cyclophosphamide) enhanced the therapeutic response, possibly by inhibiting the proliferation of both androgendependent and androgen-independent cells. These preclinical observations led to clinical trials investigating the benefits of adjuvant hormonal therapy and chemotherapy.…”