Daniel H. Shevrin

A phase II study of continuous infusion 5‐fluorouracil in advanced hormone refractory prostate cancer: An Illinois cancer center study

Background. 5‐Fluorouracil (5‐FU) has been previously associated with therapeutic benefit in hormone refractory prostate cancer. However, no previous study has administered 5‐FU as a prolonged continuous infusion, which may be the optimal schedule for this cell‐cycle specific agent.

In vivo andin vitro approaches to study metastasis in human prostatic cancer

SummaryProstate cancer is the most common malignancy in American males and is second only to lung cancer as a cause of death in the United States. Clinically, radical prostatectomy offers a patient with locally contained disease an excellent chance for cure. For patients with metastatic disease, the current therapies are merely palliative. Understanding the biology of prostate cancer metastasis should facilitate the development of novel and effective therapeutic modalities. Crucial to this objective is the availability of human tumor systems in which the biology of metastasis can be studied. The present chapter will briefly assess variousin vivo andin vitro approaches to study metastasis in human prostate cancer. Utilization of athymic nude mice has played an important role in maintaining human prostatic cancer cells as xenografts and has provided an opportunity to establish site-specific subpopulations of the parental cell lines for further characterization and investigation. At present, a few established cell lines have been useful for this purpose. Fresh tumor specimens, unfortunately, have shown limited ability to grow in nude mice. The recent development of novel approaches to permit the maintenance of freshly harvested prostate cancers has been encouraging. The use of reconstituted basement membrane (Matrigel) for co-injection with cancer cells into the subcutaneous tissues has supported growth of biologically indolent tumors. Another approach is to administer tumor cells orthotopically into the prostate of recipient nude mice. Bone marrow metastases in nude mice have been rare in the past. Recently, three approaches have been shown to be successful in accomplishing bony metastasis with PC-3 cells. They include intrasplenic injection, tail vein injection with vena cava occlusion, and tail vein injection into SCID (severe combined immunodeficient) mice. Other routes of tumor cell injection are also useful for the establishment of various organ-related metastatic subpopulations derived from unselected parental cell lines. The use of a modified Boyden chamber assay system has offered a rapidin vitro assessment of the invasive potential of specific cancer cell lines. The variousin vivo andin vitro approaches described in the present chapter make it possible to enrich site-specific variants of different prostatic cancer cell lines for further characterization and elucidation of the molecular mechanisms underlying metastasis in prostate cancer. These approaches also provide an opportunity for testing and developing novel therapeutic modalities.

Assessment of coagulation system activation using spot urine measurements.

Coagulation system activation is most commonly assessed by measuring levels of one or more proteins in peripheral blood. Because faulty blood-drawing can cause activation of the coagulation system, artifactual elevations of such markers have been reported. We have therefore investigated the possibility of using randomly collected (spot) urine samples as a non-invasive means of assessing the state of coagulation system activation. Using a commercially available enzyme-linked immunosorbent assay kit designed to measure plasma levels of fragment 1 + 2, we found immunoreactive fragment 2 in healthy control subjects, and significantly increased levels in diabetic and non-diabetic pregnant subjects, and patients with venous thromboembolism, prostate cancer, and diabetes. Measurements of excretion of immunoreactive fragment 2 are worth further study as an adjunct or alternative to plasma-based assays designed to detect or quantify coagulation system activation.

Phase I/II trial of vinorelbine and divided-dose carboplatin in advanced non-small cell lung cancer

Vinorelbine administered in a doublet with cisplatin has become a standard treatment in patients with advanced non-small cell lung cancer (NSCLC). However, carboplatin appears to provide comparable efficacy with a better nonhematologic safety profile than cisplatin. Herein we report the results of a phase I/II trial of weekly vinorelbine and divided-dose carboplatin in patients with stage IIIB/IV NSCLC, Eastern Cooperative Oncology Group performance status < or = 2, and adequate bone marrow. Patients received vinorelbine starting at 20 mg/m(2) (to 25 mg/m(2)) and carboplatin area under the curve (AUC) 2.5 in divided-doses, both given on Days 1 and 8 every 21-day cycle for up to 6 cycles or until disease progression. Dose-limiting toxicity was defined for Cycles 1 and 2. Tumor response and toxicity were assessed using standard criteria. Twenty-one patients with a mean age of 67 years (range, 43-79) and stage IIIB/IV (8/13) disease were enrolled. All but 1 patient were chemotherapy-nai;ve; the majority (n = 20) had good performance status (< or = 1). Seventy-nine courses (median, 4) were administered. The vinorelbine/carboplatin doublet was well tolerated, with 7 courses interrupted or delayed because of toxicity. Toxicities were generally mild and evenly divided between hematologic (i.e., neutropenia) and nonhematologic (i.e., fatigue). No growth factor support was required for hematologic toxicity. There was only one case of grade 2 alopecia, and no cases of > or = grade 2 neurotoxicity. There were 5 (24%) partial responses, and 9 (43%) patients had stable disease. Weekly vinorelbine 25 mg/m(2) and divided-dose carboplatin AUC 2.5 is a well tolerated regimen with activity in advanced NSCLC patients. Further evaluation of this regimen in combination with novel targeted biologic therapy is warranted.