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Background and Objectives: Low-grade non-Hodgkin's lymphoma (NHL) remains incurable with standard dose chemotherapy. Nucleoside analogs such as fludarabine are effective, but even when used as initial therapy, the median duration of remission ranges from only 16 to 24 months. Interferon (IFN) is also active and has been investigated both by incorporating it into the chemotherapy regimen and/or as maintenance therapy, where it may prolong remission. We designed a phase II trial of alternating fludarabine and IFNalpha2a to determine response rate, time to progression and toxicity of this regimen in patients with advanced stage low-grade NHL or mantle cell lymphoma., Design and Methods: Patients had received 0-2 prior regimens that did not include nucleoside analogs or IFN and had adequate organ function. Fludarabine was administered intravenously at 25 mg/m2/day for 5 days once every 6 weeks with IFN in weeks 4 and 5 at 3x10(6) U/m2 subcutaneously three times weekly for 6 doses. Treatment continued in responders for 2 cycles past maximal response (minimum 6 cycles). No maintenance was given., Results: Between 1994 and 1999, 31 patients were accrued and were evaluable for toxicity, with 29 eligible for evaluation of response. Toxicity was primarily myelosuppression, with grade 3 neutropenia in 12 patients and grade 4 thrombocytopenia in one patient. The overall response rate was 51.7% (15/29), including 6 complete and 9 partial responses. With a median follow-up of 35.6 months, the median overall survival was 60.8 months, and the median time to disease progression (TTP) was 12.6 months. Of the 15 responding patients, treatment-naive patients had a median response duration of 39.6 months with a median TTP of 42.1 months, while the median response duration was 5.2 months with a median TTP of 14.5 months in patients who had received prior treatment (p=0.0065 and 0.0374, respectively)., Interpretation and Conclusions: This schedule of alternating fludarabine with IFN does not seem to increase response rate appreciably, but there are some prolonged responses, particularly in previously untreated patients. Given the non-overlapping toxicities of IFN with those of chemotherapy and antibody-based therapeutics, there may be a role for combination therapies, especially if the biological basis of response to IFN can be elucidated.

Background: It is well known that metastatic renal cell carcinoma (RCC) exhibits constitutive resistance to chemotherapeutic agents. Antimicrotubule agents such as vinblastine are associated with low but reproducible response rates (approximately 12%) in patients with RCC. Estramustine has been shown to potentiate the antimicrotubule effects of vinblastine. The authors sought to increase the activity of vinblastine in RCC through the addition of estramustine., Methods: Twenty-one patients with metastatic RCC not previously treated with chemotherapy received oral estramustine phosphate, 600 mg/m(2), on Days 1, 2, and 3 weekly for 6 weeks, and intravenous vinblastine, 4 mg/m(2) on Day 2 weekly for 6 weeks, repeated every 8 weeks. Twenty-one patients received 31 cycles of therapy., Results: Two patients experienced Grade 3 and 4 hematologic toxicity, and three patients had Grade 3 nonhematologic toxicity consisting of neurologic toxicity, hepatic toxicity, or angioneurotic edema. One patient had a partial response with decreased liver metastases for 48 weeks; 9 patients had stable disease, for a median duration of 14 weeks (range, 11-31 weeks); and 11 patients demonstrated disease progression. The median overall time to progression was 8 weeks and the median overall survival period was 24 weeks., Conclusions: Although well tolerated, the combination of oral estramustine phosphate with vinblastine administered on this schedule had minimal activity in patients with metastatic RCC., (Copyright 2003 American Cancer Society.)

Anticipating the development of lung cancer early detection programs, we examined the: (1) feasibility of a lung cancer early detection program; (2) characteristics of enrollees (e.g. motivation to quit smoking); (3) correlates of enrollee motivation to quit smoking; and (4) rates of smoking cessation following screening. Brief surveys were completed before and after screening, which involved sputum cytology, chest X-ray, bronchoscopy, spiral CT, and a meeting with an oncologist to discuss smoking cessation. Of the 168 eligible women who were heavy smokers recruited via newspaper and cancer center advertisements, 55 agreed to undergo screening. Enrollees showed low-to-moderate levels of quit motivation and high levels of nicotine addiction; enrollees were interested in a range of smoking cessation treatments; 20% of enrollees exhibited clinical-levels of emotional distress; 64% of enrollees reported low levels of self-efficacy (i.e. self-confidence) to quit; 24% of enrollees reported low levels of quitting pros and 25% reported high levels of quitting cons; 31% of enrollees showed high levels of fatalistic beliefs about cancer; and all enrollees recognized their elevated lung cancer risk. Greater motivation to quit smoking was related to: greater age, lower nicotine addiction, fewer health symptoms, and higher quitting self-efficacy and quitting pros. Finally, 16% of enrollees quit smoking after screening. Overall, many women eligible for screening refused to undergo comprehensive screening that included bronchoscopy and spiral CT. Screening may represent an opportunity for quitting smoking, although more intensive smoking cessation interventions that target nicotine addiction and self-efficacy may be needed to maximize the health benefits of an early detection program., (Copyright 2002 Elsevier Science Ireland Ltd.)

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is a synthetic dithiolethione with chemopreventive activity against carcinogen-induced neoplasia of liver, lung, and colon in several animal model systems. Protection from tumor formation is associated with elevation of Phase II enzymes, including glutathione (GSH) transferase and NAD(P)H:quinone oxidoreductase (DT-diaphorase) in experimental carcinogenesis models in vivo. To investigate the time and dose relationships of the pharmacological action of oltipraz and to develop a model for its investigation, a human colon adenocarcinoma HT29 cell line was primarily used. In this cell line, oltipraz resulted in increased activity of both GSH transferase and DT-diaphorase. At the maximum effective concentration (100 microM), the elevation of GSH transferase was 3-fold and that of DT-diaphorase was 2-fold. The optimal duration of oltipraz exposure to HT29 cells was 24 h, following which the peak in enzyme activity was observed at 24 h after removal of the drug, and activity had almost returned to control levels after 72 h in drug-free media. Steady-state mRNA levels for DT-diaphorase were observed to increase during the period of drug exposure and remained elevated, even as catalytic activities declined to control levels, suggesting additional mechanisms for control of the activity of this enzyme. More prolonged drug exposure was associated with less induction of the detoxication enzymes, prompting an investigation of the possible toxicity of oltipraz to these cells. Although the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed inhibition of proliferation (IC50, 100 microM oltipraz), a clonogenic assay demonstrated no loss of clonogenicity. Oltipraz is known to be extensively metabolized in many species; two major metabolites include a 3-ketone (metabolite 2, M2) and a molecular rearrangement to a pyrrolopyrazine derivative (metabolite 3, M3), numerous conjugates of which are formed in vivo. To investigate the potential cause of the lag in response, we synthesized two major oltipraz metabolites (M2 and M3) and tested their efficacy in enzyme induction. The activity of DT-diaphorase was induced similarly by both oltipraz and M2 (2.6- versus 2.8-fold baseline) at 100 microM, whereas M3 was inactive at all concentrations. M2 also resulted in a 5.8-fold elevation of steady-state DT-diaphorase mRNA levels. Both enzyme activity and steady-state mRNA peaked at 24 h as with the parent compound. Thus, the oxidative desulfuration of oltipraz results in the formation of an active metabolite, but this process is not rate limiting for the induction of detoxicating enzymes. These data support the use of intermittent schedules in oltipraz in clinical trials of chemoprevention because of evidence of attenuation of response. The metabolite M2, but not M3, is as active as the parent compound and may be considered for clinical development in its own right.

The development of time-dependent pharmacodynamic models in cancer chemotherapy has been extremely limited. A population approach was used to develop such a model to describe the effect of buthionine sulfoximine (BSO), via its active S-isomer (S-BSO), on glutathione (GSH) depletion in peripheral mononuclear cells. The Phase I trial utilized escalating doses of BSO, from 5 to 17 gm/m2, as a multiple infusion regimen. The population model consisted of a linear 2-compartment pharmacokinetic model coupled to an indirect response model. The indirect response model consisted of a GSH compartment with input and output rate processes that are modulated as a function of S-BSO and GSH concentrations. The model predicted the observed gradual depletion of GSH, a nadir at approximately 30 h after the last dose of BSO, and a return to baseline GSH levels. On the basis of an IC50 estimate of about 1.6 microM for inhibition of gamma-glutamylcysteine synthetase, the target enzyme of BSO, the population model predicted near identical GSH concentration time profiles over the dose range studied. Time-dependent pharmacodynamic models are seen as a powerful means to design dosing regimens and to provide a mathematical platform for mechanistic based models.

The topoisomerase I inhibitor topotecan is a potent water-soluble camptothecin derivative with activity in a wide variety of preclinical models. Topotecan exhibits schedule dependency in vivo, with the greatest activity being observed on repeated dose schedules. On the basis of the initial clinical studies that showed a short plasma half-life, we attempted to prolong drug exposure by giving topotecan as a 24-h infusion weekly. In a phase I trial, we treated 32 patients at doses ranging from 1.0 to 2.0 mg/m2. The patient population had not been heavily pretreated with chemotherapy and was of good performance status. The incidence of neutropenia, which was dose-limiting, increased sharply with relatively small increments in dose. Doses greater than 1.5 mg/m2 were associated with nadirs that developed after one to three weekly treatments. A patient with metastatic colorectal cancer had a prolonged partial response. The plasma pharmacokinetics of topotecan (lactone and open forms) was characterized in 21 patients. Mean plasma steady-state drug levels were proportional to the dose and were within the range required to exert cytotoxicity in preclinical models. Plasma elimination curves were fit to a one-compartment model, in which the harmonic mean half-life of topotecan was 3.5 h. The ratio of the lactone to the total drug concentrations was constant throughout, which suggests that for this schedule the total drug concentration may be used as a measure of active lactone exposure. This conclusion is supported by the pharmacodynamic analysis, which revealed a positive correlation of both lactone and total drug steady-state concentrations with bone marrow toxicity. The further investigation of this and other infusional schedules in phase II trials will be conducted. The steady-state concentrations of total drug will be measured in several of these trials to establish its potential role in adaptive dosing using this schedule. Such a strategy is justified by the interpatient variability in toxicity and the steep dose-response curve observed in this study. Preliminary evidence of interpatient variability in the mRNA expression of topoisomerase I in the peripheral mononuclear cells and colon mucosa is presented. Trials are under way using biological endpoints for further selection of patients in whom the use of topoisomerase inhibitors may be therapeutically beneficial.

Infection of Pekin ducks with duck hepatitis B virus is a useful model for studying the hepadenoviruses, of which human hepatitis B virus is the prototype. The utility of this model has been limited, however, by the difficulties associated with anesthetizing and obtaining liver biopsies from ducks. We developed a technique using Telazol (13 mg/kg) to anesthetize ducks before surgical biopsy of the liver in ducks infected with duck hepatitis B virus. Eight Pekin ducks infected with duck hepatitis B virus underwent serial biopsies at 4- to 5-week intervals. There was one perioperative death in 34 surgical procedures with no evidence on intra-abdominal sepsis or wound complications. Telazol can be used safely and humanely to anesthetized ducks without the need for general endotracheal anesthesia.

Sera from 588 woodchucks were assayed for woodchuck hepatitis virus (WHV) markers using hepatitis B virus (HBV) reagents which have cross-reactivity with WHV markers. Twenty per cent of these woodchucks, trapped in Delaware, Maryland and Pennsylvania, had WHsAg; 50% of these had DNA polymerase. There are areas of high and low endemicity within these states. Female woodchucks may have a higher incidence of WHV markers than do males. Woodchuck hepatitis surface antigen (WHsAg) and anti-WHc often occur together but less commonly than HBsAg and anti-HBc do in human HBV infection. Experimental infection of woodchucks with WHV produced a prolonged infection (up to 40 weeks). WHsAg and DNA polymerase appeared to be more reliable indicators of infectivity than anti-WHc, woodchuck hepatitis e antigen (WHeAg) or anti-WHe. WHeAg was not detected throughout this period of infection, while anti-WHe appeared late in two of three experimentally infected animals. Four male and four female woodchucks which developed primary hepatocellular carcinoma in captivity were analyzed for WHV markers throughout their period of confinement. Seven were WHsAg and anti-WHc positive when captured. The animal that was free of WHV markers on capture converted to the WHsAg and anti-WHc positive state prior to the development of primary hepatocellular carcinoma. One primary hepatocellular carcinoma animal produced WHeAg and none anti-WHs or anti-WHe.

The tumor-inhibitory effect of an intralesional injection of Propionibacterium acnes was of limited duration ("finite"). Our model was the DBA/2 syngeneic mouse injected with P815 mastocytoma cells (5 X 10(5)) into each rear footpad; only the left was treated, leaving the right as a "pseudometastasis." The finite effect occurred at approximately 21 days after the first treatment. Subsequent i.p. treatments with P. acnes did not alter this effect, although they increased mean survival time. With one footpad tumor, we achieved 22% cures with complete regression and no sign of metastatic growth. A RNA fraction from P. acnes produced inhibition of tumor growth, but crude cell walls and cell walls treated with Pronase had no effect. A P. acnes cytoplasmic fraction with tumor-inhibitory activity was pelleted by high-speed centrifugation; this fraction inhibited P815 mastocytoma as fully as whole cells injected in one-fifth the dose on a nitrogen basis and did not cause a local inflammatory reaction. The activity of the pellet also differed from whole cells in that it was equally inhibitory to the pseudometastasis in the contralateral right rear footpad. The cytoplasmic fraction apparently contained at least two active components since activity was obtained at two dilution levels. Such activity was relatively stable at 5 degrees, but it was unstable at -30 degrees.

Woodchuck sera were tested for antigens and antibodies with tests which detect human hepatitis virus antigens and antibodies. Data on 264 woodchuck sera are presented.