The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies

John W. Smith, Walter J. Urba, Brendan D. Curti, Lori J. Elwood, Ronald G. Steis, John E. Janik, William Sharfman, Langdon L. Miller, Robert G. Fenton, Kevin C. Conlon, Mario Sznol, Stephen P. Creekmore, Nancy F. Wells, Francis W. Ruscetti, Jonathan R. Keller, Kjetil Hestdal, Masanao Shimizu, Jeffrey Rossio, W. Gregory Alvord, Joost J. OppenheimDan L. Longo

Research output: Contribution to journalArticle

Abstract

Purpose: A phase I trial was undertaken because interleukin-1 alpha (IL-1α) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. Patients and Methods; In this phase I trial, IL-1α was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. Results: The maximum-tolerated dose (MTD) of IL-1α alone was 0.3 μg/kg. A second group of patients received indomethacin plus IL-la based on preclinical studies, which indicated that indomethacin could abrogate IL-1α-induced hypotension; however, the MTD of IL-1α plus indomethacin was 0.1 μg/kg lower than IL-1α alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 μg/kg IL-1α. Dose-limiting toxicities included hypotension, myo-cordial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1α treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1α treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. Conclusion: We conclude that at doses of IL-1α that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.

Original languageEnglish (US)
Pages (from-to)1141-1152
Number of pages12
JournalJournal of Clinical Oncology
Volume10
Issue number7
StatePublished - 1992
Externally publishedYes

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Interleukin-1alpha
Poisons
Neoplasms
Indomethacin
Maximum Tolerated Dose
Hypotension
Controlled Hypotension
Therapeutics
Confusion
Chills
Megakaryocytes
Myalgia
Myeloid Cells
Thyrotropin
Protein C
Platelet Count
Vascular Resistance
C-Reactive Protein
Infarction
Nausea

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Smith, J. W., Urba, W. J., Curti, B. D., Elwood, L. J., Steis, R. G., Janik, J. E., ... Longo, D. L. (1992). The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. Journal of Clinical Oncology, 10(7), 1141-1152.

The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. / Smith, John W.; Urba, Walter J.; Curti, Brendan D.; Elwood, Lori J.; Steis, Ronald G.; Janik, John E.; Sharfman, William; Miller, Langdon L.; Fenton, Robert G.; Conlon, Kevin C.; Sznol, Mario; Creekmore, Stephen P.; Wells, Nancy F.; Ruscetti, Francis W.; Keller, Jonathan R.; Hestdal, Kjetil; Shimizu, Masanao; Rossio, Jeffrey; Gregory Alvord, W.; Oppenheim, Joost J.; Longo, Dan L.

In: Journal of Clinical Oncology, Vol. 10, No. 7, 1992, p. 1141-1152.

Research output: Contribution to journalArticle

Smith, JW, Urba, WJ, Curti, BD, Elwood, LJ, Steis, RG, Janik, JE, Sharfman, W, Miller, LL, Fenton, RG, Conlon, KC, Sznol, M, Creekmore, SP, Wells, NF, Ruscetti, FW, Keller, JR, Hestdal, K, Shimizu, M, Rossio, J, Gregory Alvord, W, Oppenheim, JJ & Longo, DL 1992, 'The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies', Journal of Clinical Oncology, vol. 10, no. 7, pp. 1141-1152.
Smith, John W. ; Urba, Walter J. ; Curti, Brendan D. ; Elwood, Lori J. ; Steis, Ronald G. ; Janik, John E. ; Sharfman, William ; Miller, Langdon L. ; Fenton, Robert G. ; Conlon, Kevin C. ; Sznol, Mario ; Creekmore, Stephen P. ; Wells, Nancy F. ; Ruscetti, Francis W. ; Keller, Jonathan R. ; Hestdal, Kjetil ; Shimizu, Masanao ; Rossio, Jeffrey ; Gregory Alvord, W. ; Oppenheim, Joost J. ; Longo, Dan L. / The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. In: Journal of Clinical Oncology. 1992 ; Vol. 10, No. 7. pp. 1141-1152.
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abstract = "Purpose: A phase I trial was undertaken because interleukin-1 alpha (IL-1α) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. Patients and Methods; In this phase I trial, IL-1α was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. Results: The maximum-tolerated dose (MTD) of IL-1α alone was 0.3 μg/kg. A second group of patients received indomethacin plus IL-la based on preclinical studies, which indicated that indomethacin could abrogate IL-1α-induced hypotension; however, the MTD of IL-1α plus indomethacin was 0.1 μg/kg lower than IL-1α alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 μg/kg IL-1α. Dose-limiting toxicities included hypotension, myo-cordial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1α treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1α treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. Conclusion: We conclude that at doses of IL-1α that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.",
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T1 - The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies

AU - Smith, John W.

AU - Urba, Walter J.

AU - Curti, Brendan D.

AU - Elwood, Lori J.

AU - Steis, Ronald G.

AU - Janik, John E.

AU - Sharfman, William

AU - Miller, Langdon L.

AU - Fenton, Robert G.

AU - Conlon, Kevin C.

AU - Sznol, Mario

AU - Creekmore, Stephen P.

AU - Wells, Nancy F.

AU - Ruscetti, Francis W.

AU - Keller, Jonathan R.

AU - Hestdal, Kjetil

AU - Shimizu, Masanao

AU - Rossio, Jeffrey

AU - Gregory Alvord, W.

AU - Oppenheim, Joost J.

AU - Longo, Dan L.

PY - 1992

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N2 - Purpose: A phase I trial was undertaken because interleukin-1 alpha (IL-1α) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. Patients and Methods; In this phase I trial, IL-1α was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. Results: The maximum-tolerated dose (MTD) of IL-1α alone was 0.3 μg/kg. A second group of patients received indomethacin plus IL-la based on preclinical studies, which indicated that indomethacin could abrogate IL-1α-induced hypotension; however, the MTD of IL-1α plus indomethacin was 0.1 μg/kg lower than IL-1α alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 μg/kg IL-1α. Dose-limiting toxicities included hypotension, myo-cordial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1α treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1α treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. Conclusion: We conclude that at doses of IL-1α that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.

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