Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy

Increased efficacy in the rat prostate cancer model

Andrew V Schally, A. I. Kook, E. Monje, T. W. Redding, J. I. Paz-Bouza

Research output: Contribution to journalArticle

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Abstract

The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with the chemotherapeutic agent Novantrone (mitoxantrone dihydrochloride) was studied in the Dunning R3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 μg/day were injected intramuscularly once a month. Novantrone (0.25 mg/kg) was injected intravenously once every 3 weeks. Three separate experiments were carried out. When the therapy was started 45 days after transplantation and continued for 70 days, tumor volume in the presence of the microcapsules (966 ± 219 mm3) or Novantrone (3606 ± 785 mm3) given alone was significantly decreased compared to controls (14,476 ± 3045 mm3). However, the combination of microcapsules and Novantrone caused a greater inhibition of tumor growth (189 ± 31 mm3) than the single agents. Similar effects were seen when the percent increase in tumor volume was examined. Tumor volume increased 10,527 ± 1803% for the control group. The inhibition of growth caused by the [D-Trp6]LH-RH microcapsules alone (672 ± 153% increase in volume) was again greater than that caused by Novantrone alone (2722 ± 421% increase). The combination of the two agents was again the most effective, resulting in an increase in tumor volume of only 105 ± 29%. Control tumors weighed 30.0 ± 6.5 g. Tumor weights were much less in the groups treated with either microcapsules (3.28 ± 0.69 g) or Novantrone (19.53 ± 3.3 g) alone. The lowest tumor weights after 70 days of treatment were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and Novantrone (1.02 ± 0.2 g). Testes and ventral prostate weights were significantly diminished by the administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Novantrone. In both of these groups, luteinizing hormone and prolactin levels were reduced and serum testosterone was suppressed to undetectable levels. Similar results were obtained in two other experiments in which the duration of treatment was 60 or 105 days. These results suggest that the overall response could reflect the inhibition of proliferation of hormone-independent cancer cells by Novantrone in addition to the suppressive effect of [D-Trp6]LH-RH on the growth of androgen-dependent tumor cells. The administration of Novantrone in combination with microcapsules of [D-Trp6]LH-RH might produce a better clinical response than LH-RH analog alone in patients with advanced prostate carcinoma.

Original languageEnglish
Pages (from-to)8764-8768
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume83
Issue number22
DOIs
StatePublished - Dec 1 1986
Externally publishedYes

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Mitoxantrone
Gonadotropin-Releasing Hormone
Prostatic Neoplasms
Capsules
Drug Therapy
Tumor Burden
Prostate
Neoplasms
Growth
Polyglactin 910
Therapeutics
Luteinizing Hormone
Tryptophan
Prolactin
Androgens
Testosterone
Testis
Transplantation
Hormones

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy: Increased efficacy in the rat prostate cancer model",
abstract = "The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with the chemotherapeutic agent Novantrone (mitoxantrone dihydrochloride) was studied in the Dunning R3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 μg/day were injected intramuscularly once a month. Novantrone (0.25 mg/kg) was injected intravenously once every 3 weeks. Three separate experiments were carried out. When the therapy was started 45 days after transplantation and continued for 70 days, tumor volume in the presence of the microcapsules (966 ± 219 mm3) or Novantrone (3606 ± 785 mm3) given alone was significantly decreased compared to controls (14,476 ± 3045 mm3). However, the combination of microcapsules and Novantrone caused a greater inhibition of tumor growth (189 ± 31 mm3) than the single agents. Similar effects were seen when the percent increase in tumor volume was examined. Tumor volume increased 10,527 ± 1803{\%} for the control group. The inhibition of growth caused by the [D-Trp6]LH-RH microcapsules alone (672 ± 153{\%} increase in volume) was again greater than that caused by Novantrone alone (2722 ± 421{\%} increase). The combination of the two agents was again the most effective, resulting in an increase in tumor volume of only 105 ± 29{\%}. Control tumors weighed 30.0 ± 6.5 g. Tumor weights were much less in the groups treated with either microcapsules (3.28 ± 0.69 g) or Novantrone (19.53 ± 3.3 g) alone. The lowest tumor weights after 70 days of treatment were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and Novantrone (1.02 ± 0.2 g). Testes and ventral prostate weights were significantly diminished by the administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Novantrone. In both of these groups, luteinizing hormone and prolactin levels were reduced and serum testosterone was suppressed to undetectable levels. Similar results were obtained in two other experiments in which the duration of treatment was 60 or 105 days. These results suggest that the overall response could reflect the inhibition of proliferation of hormone-independent cancer cells by Novantrone in addition to the suppressive effect of [D-Trp6]LH-RH on the growth of androgen-dependent tumor cells. The administration of Novantrone in combination with microcapsules of [D-Trp6]LH-RH might produce a better clinical response than LH-RH analog alone in patients with advanced prostate carcinoma.",
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T1 - Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy

T2 - Increased efficacy in the rat prostate cancer model

AU - Schally, Andrew V

AU - Kook, A. I.

AU - Monje, E.

AU - Redding, T. W.

AU - Paz-Bouza, J. I.

PY - 1986/12/1

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N2 - The combination of hormonal treatment based on a long-acting delivery system for the agonist [6-D-tryptophan]luteinizing hormone-releasing hormone ([D-Trp6]LH-RH) with the chemotherapeutic agent Novantrone (mitoxantrone dihydrochloride) was studied in the Dunning R3327H rat prostate cancer model. Microcapsules of [D-Trp6]LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 μg/day were injected intramuscularly once a month. Novantrone (0.25 mg/kg) was injected intravenously once every 3 weeks. Three separate experiments were carried out. When the therapy was started 45 days after transplantation and continued for 70 days, tumor volume in the presence of the microcapsules (966 ± 219 mm3) or Novantrone (3606 ± 785 mm3) given alone was significantly decreased compared to controls (14,476 ± 3045 mm3). However, the combination of microcapsules and Novantrone caused a greater inhibition of tumor growth (189 ± 31 mm3) than the single agents. Similar effects were seen when the percent increase in tumor volume was examined. Tumor volume increased 10,527 ± 1803% for the control group. The inhibition of growth caused by the [D-Trp6]LH-RH microcapsules alone (672 ± 153% increase in volume) was again greater than that caused by Novantrone alone (2722 ± 421% increase). The combination of the two agents was again the most effective, resulting in an increase in tumor volume of only 105 ± 29%. Control tumors weighed 30.0 ± 6.5 g. Tumor weights were much less in the groups treated with either microcapsules (3.28 ± 0.69 g) or Novantrone (19.53 ± 3.3 g) alone. The lowest tumor weights after 70 days of treatment were obtained in the group that received the combination of [D-Trp6]LH-RH microcapsules and Novantrone (1.02 ± 0.2 g). Testes and ventral prostate weights were significantly diminished by the administration of microcapsules of [D-Trp6]LH-RH alone or in combination with Novantrone. In both of these groups, luteinizing hormone and prolactin levels were reduced and serum testosterone was suppressed to undetectable levels. Similar results were obtained in two other experiments in which the duration of treatment was 60 or 105 days. These results suggest that the overall response could reflect the inhibition of proliferation of hormone-independent cancer cells by Novantrone in addition to the suppressive effect of [D-Trp6]LH-RH on the growth of androgen-dependent tumor cells. The administration of Novantrone in combination with microcapsules of [D-Trp6]LH-RH might produce a better clinical response than LH-RH analog alone in patients with advanced prostate carcinoma.

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