Showing papers by "Walter M. Stadler published in 1998"

Overcoming cellular senescence in human cancer pathogenesis

Abstract: Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and -3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11-q12 (0.99) and +8p22-pter (0.94) in the immortal muscle invasive TCCs, and of -9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13-p14. In this study, four of six myoinvasive TCCs also showed TP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably, TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11-q12, -3p13-p14, or -8p21-pter.

Multicenter phase II trial of interleukin-2, interferon-alpha, and 13-cis-retinoic acid in patients with metastatic renal-cell carcinoma.

Abstract: PURPOSETo determine the response rate and toxicity of oral 13-cis-retinoic acid (CRA) added to an outpatient regimen of subcutaneous interleukin-2 (IL2) and interferon-alpha (IFNA) in previously untreated patients with metastatic renal-cell carcinoma (RCC).PATIENTS AND METHODSEligibility included a performance status of 2 or better, no significant end-organ dysfunction, and written informed consent. Characteristics of 47 of 48 assessable patients included a median performance status of 0, prior nephrectomy in 68% of patients, one metastatic site in 30% of patients, and lung-only metastatic disease in 21% of patients. Therapy consisted of IL2 11 x 10(6) IU 4 days per week for 4 weeks, IFNA 9 x 10(6) IU 2 days per week for 4 weeks, and CRA 1 mg/kg daily on a 6-week cycle.RESULTSEight of 47 patients (17%) responded (one complete response, seven partial responses). Three partial responders were rendered disease free by subsequent surgical resection. Four additional patients experienced a minor response in lun...

Chromosome 17-mediated dormancy of AT6.1 prostate cancer micrometastases

Abstract: To improve the diagnosis and treatment of cancer, an increased understanding of the molecular and cellular changes that regulate metastatic ability is required. We have recently demonstrated a prostate cancer metastasis-suppressor activity encoded by a discontinuous approximately 70-cM region of human chromosome. The presence of this region suppresses the spontaneous metastatic ability of AT6.1 rat prostatic cancer cells by greater than 30-fold (M. A. Chekmareva et al., Prostate, 33: 271-280, 1997). Interestingly, a number of potentially important genes which have been mapped to human chromosome 17, including TP53, NM23, and BRCA1, are not retained (M. A. Chekmareva et al., cited above) or are not expressed in these microcell hybrids (B. A. Yoshida et al., In Vivo, in press), which suggests the presence of a novel metastasis-suppressor gene(s) or novel function of a known gene(s) encoded by this region(s). We hypothesize that identification of the "step" in the metastatic cascade that is inhibited by the presence of the approximately 70-cM metastasis-suppressor region will facilitate the identification of candidate metastasis-suppressor genes. For a cancer cell to metastasize, it must escape from the primary tumor, enter the circulation, arrest in the microcirculation, extravasate into a tissue compartment, and grow. This suppression of spontaneous macroscopic lung metastases could be due to the inhibition of a number of steps within this cascade. Results of the current study demonstrate that AT6.1 cells containing the approximately 70-cM region (AT6.1-17-4 cells) escape from the primary tumor and arrest in the lung but are growth-inhibited unless the metastasis-suppressor region is lost. This growth inhibition seems to result from an effect of one or more genes at the metastatic site and not from a circulating angiogenesis inhibitor. Our findings suggest that the approximately 70-cM region of human chromosome 17 may encode a gene(s) that regulates the "dormancy" of AT6.1-17-4 micrometastases.

Study of cohort-specific consent and patient control in phase I cancer trials.

Abstract: PURPOSETo address the challenging ethical dilemmas created from the participation of advanced cancer patients in phase I trials, we assessed the feasibility of a clinical trial design that uses an interactive informed consent process in which patient-subjects can choose to become directly involved in decisions of dose escalation.PATIENTS AND METHODSSubjects were advanced cancer patients in the Hematology/Oncology Clinics at the University of Chicago who were eligible to participate in a phase I trial in which they underwent a three-step informed consent process that used cohort-specific consent and allowed them the option to choose their own doses of the chemotherapeutic agents under study, vinorelbine (NVB) and paclitaxel (TAX), within predetermined limits. NVB and TAX were administered in conventional 21- to 28-day cycles for two cycles while on study. Dose escalation occurred when a patient-subject chose a higher untested dose after they received information on all previously assessable patient-subject...

Granulocyte-macrophage--colony stimulating factor in metastatic renal cell carcinoma: a phase II trial.

Abstract: BACKGROUND Due to lack of success with standard chemotherapy and only modest success with immunotherapy, metastatic renal cell carcinoma (RCC) is associated with a poor prognosis. Granulocyte-macrophage-colony stimulating factor (GM-CSF) is a cytokine with potential antitumor activity, including stimulation of tumor necrosis factor (TNF) and interleukin-1 secretion. It is also a potent growth factor for and activator of antigen-presenting dendritic cells. GM-CSF toxicity may be mediated by TNF, and inhibition of TNF release by pentoxifylline (PTX) may ameliorate these toxic effects. The authors conducted a Phase II trial to determine the activity of GM-CSF in metastatic RCC and to study the effect of PTX on GM-CSF toxicity. METHODS Twenty-four eligible patients with metastatic RCC received 10 μg/kg of GM-CSF per day, administered subcutaneously, on a 14-days-on/14-days-off schedule. Twelve patients received concurrent PTX at a dose of 400 mg administered orally 4 times per day. RESULTS One patient experienced prolonged stability of disease after having progressive disease on entry. Two other patients experienced substantial slowing of their progressive disease while on study. One of these patients had rapidly progressing metastases on other immunotherapy before receiving GM-CSF. Toxicity was not diminished in patients treated with PTX; it included hyperleukocytosis, nausea, vomiting, pain, fever, skin reactions, myalgia, and fatigue. CONCLUSIONS GM-CSF at the dose and schedule described in this report has minor activity against metastatic RCC, and PTX does not ameliorate its side effects. Cancer 1998;82:1352-8. © 1998 American Cancer Society.

Prostate cancer metastasis-suppressor genes: a current perspective.

Abstract: Prostate cancers account for 43% of all cancers diagnosed in American men. It is estimated that in 1996, 317,000 new cases of prostate cancer were diagnosed and 41,000 men died of the disease. The challenge of treating prostate cancer lies in accurately distinguishing those histologically-localized cancers which will complete metastatic progression from those that will remain indolent. At this time, we lack appropriate histological markers to make such distinctions, therefore, it is often difficult to accurately predict the clinical course of an individual patient's disease. There is growing evidence that a critical event in the progression of a tumor cell from a non-metastatic to metastatic phenotype is the loss of function of metastasis-suppressor genes. These genes specifically suppress the ability of a cell to metastasize. Work from several groups has demonstrated that human chromosomes 8, 10, 11 and 17 encode prostate cancer metastasis suppressor activities. As a result of these efforts the first prostate cancer metastasis-suppressor gene, KAI1, was identified and mapped to the p11-2 region of chromosome 11. In subsequent studies, an additional gene encoded by the same region, CD44 was also determined to have metastasis-suppressor activity. Recent studies have shown a correlation between decreased expression of KAI1 and CD44 and an increased malignant potential of prostate cancers. It is anticipated that the identification of other metastasis suppressor genes may allow for the development of diagnostic markers useful in the clinical substaging of individual tumors. This manuscript is intended to present our perspective on the importance of these genes in the understanding of prostate cancer progression. More importantly, we present new findings from our laboratory's effort to identify the metastasis-suppressor genes encoded by human chromosome 17. Specifically we report the strategy currently being used to evaluate a series of candidate genes and the approach being utilized to pinpoint the metastasis-suppressor region on human chromosome 17.

Activated calphostin C cytotoxicity is independent of p53 status and in vivo metastatic potential.

Abstract: The development of novel therapeutic agents to modulate programmed cell death independent of genetic background or malignant potential is a primary goal of modern cancer therapy. In this report, the light activation- and concentration-dependent cytotoxicity of calphostin C, a photoactivatable perylenequinone, is carefully evaluated using a series of nine well-characterized human and rodent prostate cancer cell lines representing the spectrum of disease progression (e.g., variations in metastatic ability, ploidy, and tumor suppressor gene status). Treatment of these cancer cell lines with nanomolar concentrations of calphostin C in combination with increasing amounts of light exposure established a relationship between light and dose dependence of calphostin C cytotoxicity. The induction of apoptosis is rapid, as evidenced by the fact that immediately after treatment, cells exposed to calphostin C with light activation exhibit both morphological and biochemical changes consistent with apoptosis (cellular and nuclear shrinkage and chromatin condensation). For example, 78% of cells treated with 100 nM calphostin C in combination with 2 h of light activation underwent apoptosis within 24 h of treatment. DNA ladder formation could be detected within 12 h of treatment. In the absence of light activation, treatment with calphostin C at all concentrations tested had no acute or durable cytotoxic effects in any of the cell lines. Our findings demonstrate that calphostin C cytotoxicity is strictly light dependent. Furthermore, its efficacy is independent of the genetic background, p53 status, or in vivo malignant potential of a cell, making it a suitable candidate for the treatment of heterogeneous tumor cell populations.

New chemotherapy regimens for advanced bladder cancer.

Abstract: Because of demonstrated superiority in multiple randomized trials, MVAC has become the standard therapy for metastatic or unresectable bladder cancer. However, the disappointing long-term results with this regimen have prompted the development of newer agents and regimens for this disease. These include novel antifolates, gemcitabine, taxanes, ifosfamide, and gallium nitrate. Each of these agents leads to objective responses, including complete responses in both untreated and previously treated patients. More recent reports of combination regimens using these agents suggest that response rates are equivalent to those seen with MVAC but that there is significantly less toxicity. These observations, if confirmed in randomized trials, would signify an important advance in the therapy of metastatic bladder cancer.

New chemotherapy regimens for advanced bladder cancer

Abstract: Because of demonstrated superiority in multiple randomized trials, MVAC has become the standard therapy for metastatic or unresectable bladder cancer. However, the disappointing long-term results with this regimen have prompted the development of newer agents and regimens for this disease. These include novel antifolates, gemcitabine, taxanes, ifosfamide, and gallium nitrate. Each of these agents leads to objective responses, including complete responses in both untreated and previously treated patients. More recent reports of combination regimens using these agents suggest that response rates are equivalent to those seen with MVAC but that there is significantly less toxicity. These observations, if confirmed in randomized trials, would signify an important advance in the therapy of metastatic bladder cancer.

Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer.

Abstract: Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.