Hartwig Huland

SIGNIFICANCE AND METABOLISM OF COMPLEXED AND NONCOMPLEXED PROSTATE SPECIFIC ANTIGEN FORMS, AND HUMAN GLANDULAR KALLIKREIN 2 IN CLINICALLY LOCALIZED PROSTATE CANCER BEFORE AND AFTER RADICAL PROSTATECTOMY

PURPOSEnWe studied plasma concentrations and elimination rates of prostate specific antigen (PSA) complexed to alpha1-antichymotrypsin and alpha2-macroglobulin, free PSA, total PSA (free PSA plus PSA alpha1-antichymotrypsin) and human glandular kallikrein 2 before, during and after radical retropubic prostatectomy for clinically localized prostate cancer.nnnMATERIALS AND METHODSnPlasma was collected and frozen within 10 minutes after sampling from 18 patients undergoing radical retropubic prostatectomy for prostate cancer. One sample was drawn preoperatively. Subsequent sampling intervals were 5 to 20 minutes perioperatively, 2 to 4 hours during the first 12 postoperative hours and 24 to 48 hours until postoperative day 14. Free PSA, PSA alpha1-antichymotrypsin, total PSA, PSA alpha2-macroglobulin and human glandular kallikrein 2 were measured with time resolved immunofluorometric assays.nnnRESULTSnPreoperatively PSA alpha2-macroglobulin was undetectable (less than 2 ng./ml.) in 17 of 18 patients. Human glandular kallikrein 2, free PSA and total PSA but not PSA alpha1-antichymotrypsin were significantly higher in patients with extraprostatic cancer (pT3a-pT4a, pN1) compared to those with organ confined cancer (pT2a/b). Surgical manipulation of the prostate caused no detectable elevation of human glandular kallikrein 2, PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. In contrast, a mean 9.6-fold increase (range 3.4 to 22) in free PSA was noted 5 minutes after prostatectomy. Free PSA was eliminated from plasma in a biphasic exponential pattern with an early plasma half-life of 55 minutes and a late plasma half-life of 18 hours. PSA alpha1-antichymotrypsin decreased slowly, whereas human glandular kallikrein 2 was detectable only 12 hours after prostatectomy. PSA alpha2-macroglobulin remained at insignificant, nondetectable concentrations during the entire perioperative and postoperative period.nnnCONCLUSIONSnRelease of free PSA contributes to the elevation of plasma total PSA after prostatectomy. Free PSA is enzymatically inactive as the release does not result in subsequent elevation of PSA alpha1-antichymotrypsin or PSA alpha2-macroglobulin. Biphasic exponential elimination of free PSA may be explained by rapid extracellular redistribution (early half-life) and glomerular filtration in the kidneys (late half-life). Our data suggest rapid metabolism of human glandular kallikrein 2 but do not support suggestions of the significance in vivo of complex formations with alpha2-macroglobulin as a major means to eliminate PSA from plasma in patients with clinically localized prostate cancer.

Inhalational Interleukin-2 in the Treatment of Pulmonary Metastases in Patients with Renal Cell Carcinoma

In murine models of malignancy, immunotherapy with interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TILs) has been shown to be effective therapy (1, 2, 3, 4). Early reports of use of IL-2, LAK cells, or TILs in patients with metastatic disease were promising (5, 6, 7, 8), however, use of such immunotherapy is limited by its severe side effects. At tolerable or even toxic dosages, complete responses occurred in less than 10% and partial responses generally in less than 30% of patients with metastatic renal-cell carcinoma or melanoma (9, 10, 11, 12, 13), and long-term therapy could not be used. Patients in poor general condition had to be excluded from treatment. Furthermore, during systemic therapy with IL-2 a large proportion of the cytokine is excreted by glomerular filtration. Despite the development of more sophisticated routes of systemic application (14, 15, 16, 17) systemic cytokine treatment remains toxic, and can only be given for short periods of time e.g., less than 3 to 6 months.