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Funding Source and Total Budget: Mountains, Recreation, and Conservation Authority and California Department of Transportation (CALTRANS); $65,000 Project Period: June 1997-June 2000 Underpasses have received increasing attention as a useful tool in increasing connectivity between natural areas separated by roadways. However, few studies have investigated the utility of underpasses for multiple wildlife species in a system highly fragmented by urbanization. We used track and remotely triggered camera surveys to monitor 43 underpasses across an urban wildlife corridor bisected by a series of roads. We measured a suite of landscape and structural variables to determine which factors promote or limit the exchange of large predators (coyotes and bobcats), urban mesopredators (gray fox, raccoon, and striped skunk), and ungulates (mule deer) through underpasses. Top predators were more likely and more frequent at underpasses in parts of the corridor that were wider and less fragmented. Mesopredators and ungulates were more likely and more frequent at underpasses in parts of the corridor that were narrower and more fragmented. Top predators and ungulates were more sensitive to smaller underpasses, using them less frequently, whereas mesopredators were more tolerant of underpass dimensions. In general, the landscape variables played an important role in determining both the probability and frequency of underpass use, whereas the underpass dimension variables were more important in determining the frequency of underpass use. The success of predator movement between natural areas separated by roadways will ultimately depend on situating large underpasses away from areas of high road density and residential development. Wider corridors will allow for the continued movement of large predators across the landscape, potentially alleviating increases in mesopredator abundance. These data have played a vital role in addressing connectivity needs in southern California, as we have been working closely with the California Department of Transportation (CALTRANS) to determine the effectiveness of underpasses across the region.

Thirty-seven fully assessable patients with metastatic malignant melanoma were administered DTIC, actinomycin-D, and dibromodulcitol (DBD) on a q 3- to 4-week schedule. Doses of actinomycin-D and DTIC were 1.25 mg/m2 and 750 mg/m2, respectively, on day 1. DBD was progressively escalated in five dose levels in succeeding patients from an initial 90 mg/m2 daily, days 3-7, to a dose-limiting 230 mg/m2. Two complete and nine partial responses were observed for an overall response rate of 30%. Median duration of response was 18 weeks. Major toxicities observed were hematologic and gastrointestinal. Median survival of all patients was 30 weeks and did not differ significantly from our earlier trials of DTIC and actinomycin-D +/- chlorozotocin. Although the observed objective response rate was higher than our previous efforts in this disease, the addition of DBD failed to significantly impact on the survival of the entire treatment group. Further investigation of this chemotherapy combination does not appear warranted.

The incidence and type of hemorrhage were studied in 718 patients with solid tumors. All patients were receiving myelosuppressive chemotherapeutic agents. Seventy-five patients (10.4%) experienced one or more episodes of hemorrhage. Bleeding was due to tumor invasion in 25 patients (33.3%), was due to disseminated intravascular coagulation in seven patients (9.3%), and was unrelated to malignant neoplasms or drug treatment in six patients (8%). Thirty-seven patients (49.3%) had hemorrhages associated with drug-induced thrombocytopenia. There was a quantitative relationship between the incidence of hemorrhage and the platelet count for both the thrombocytopenic group and the total group of patients with hemorrhages from all causes. The incidence of hemorrhage was low until the platelet count decreased below 10,000/cu mm.

The B-16 melanoma animal cell line and HEC-1A human endometrial cell line treated with Nafazatrom (NFZ) (5 mu/ml) and varying doses of ionizing radiation show a dose response curve of increased colony inhibition with increasing radiation dose. The B-16 line consistently demonstrated enhanced colony inhibition when NFZ was added prior to radiation. This colony inhibition by NFZ was not seen in the HEC-1A cell line. No adverse effect, i.e., increased tumor colony growth, was evident when NFZ and radiation were combined. This study suggests that ionizing radiation can be combined with NFZ without adverse effect on the cell killing effects of either modality.

Nafazatrom was evaluated in escalating daily oral doses ranging from 0.25 to 8.0 g/m2 without producing significant toxicities. Malabsorption proved dose limiting at 8.0 g/m2 as a single daily dose, but splitting the same total dose into two or four doses circumvented this problem. Doses of 2.0 g/m2 at 6-h intervals or 4.0 g/m2 every 12 h are reasonable for Phase II and adjuvant trials. Pharmacologic evaluation of nafazatrom confirmed malabsorption at the highest single daily dose level tested and suggests that absorption was impaired in patients with extensive liver metastases.

Vindesine was tested in 23 fully evaluable patients with advanced carcinomas of the head and neck. All had received previous chemotherapy. No complete or partial responses resulted after one or more courses of 1.5 mg/m2 i.v. bolus daily X 2 days. Leukopenia was noted in 46% and peripheral neuropathy was reported in 29%. This dose-schedule of vindesine is inactive in previously treated patients with squamous carcinomas of the head and neck.

CCNU and Bleomycin, alone or in combination, were used to treat 397 evaluable cases of advanced cancer. Responses defined as 50% or greater reduction in all tumor masses occurred in 13/35 lymphomas, 8/50 brain cancers, and 28/312 other solid tumors. Hematologic toxicity of a life-threatening degree occurred in 33/298 patients evaluable for CCNU toxicity; in an additional 50 it was considered severe. Pulmonary toxicity was severe in 4 patients. Drug-associated deaths (4) included one each due to leukopenia and thrombocytopenia after CCNU; one due to pulmonary toxicity after Bleomycin; and one due to shock after the 20th dose of Bleomycin. There was no suggestion of synergism or additive activity with the two drugs.

A phase II study of dianhydrogalactitol in patients with advanced lung cancer yielded responses in three of 33 patients with adenocarcinoma and in one of 11 patients with large cell anaplastic carcinoma. Small cell and squamous cell carcinomas were unresponsive. Toxic effects were acceptable and were related to serum creatinine values.

Tricyclic nucleoside phosphate (TCN-P) was selected for clinical trials because of its unusual chemical structure and activity against L1210 murine leukemia and MX-1 mammary xenograft. Inhibiting DNA synthesis, TCN-P was more toxic during S-phase of cell cycle. A phase I study was conducted in 24 patients with advanced solid cancers. The drug was given as a slow i.v. injection over 5 min on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 12 to 96 mg/m2 were studied with 3 to 12 patients treated at each level; a total of 106 doses was administered. The major hematological toxicity was thrombocytopenia, with a median nadir occurring at Day 34 of the cycle and first appearing at doses greater than 24 mg/m2. Anemia was seen at each dose level occurring between Days 8 and 34. Non-myelosuppressive toxic effects included stomatitis, anorexia, transient fever, nausea and vomiting, and dose-limiting hyperglycemia and diarrhea. The highest tolerated dose was 48 mg/m2. Plasma, pleural fluid, urine, and tissue samples were analyzed for TCN-P and tricyclic nucleoside (TCN) in selected patients by high-performance liquid chromatography. Plasma decay curves revealed extended retention of both TCN and TCN-P. Autopsy specimens obtained 61 days after therapy showed the highest residues of TCN-P in liver metastases and of TCN in gall bladder, bile, and pancreas. No drug was detected in urine samples of two patients. Prolonged retention and erratic plasma levels of the drug are probably due to extensive enterohepatic circulation, as well as repeated interconversion between TCN-P and TCN within cells. This weekly schedule produced unexpected clinical toxicity and should not be pursued.

Sixty-one assessable patients with advanced small cell and non-small cell carcinoma of the lung were given PCNU on an intermittent every 6-week schedule. Starting doses ranged from 75 mg/m2 for poor-risk patients to 100 mg/m2 for good-risk patients, depending on the bone marrow, liver, and renal status. Six partial responses (two small cell carcinoma, two adenocarcinoma, two large cell carcinoma) of short duration were documented. The major toxic effects were thrombocytopenia (35%) and leukopenia (16%). PCNU does not appear to have sufficient antitumor activity to warrant further investigation in advanced lung cancer.

Two hundred twenty eligible patients with metastatic colorectal carcinoma were treated with a combination of beta-2'-deoxythioguanosine (BTG), plus methyl-CCNU or mitomycin. There was no significant difference in overall response (CR/PR + stable) among fully evaluable patients between the mitomycin plus BTG arm 19/96 (19.7%) and the MeCCNU arm 26/87 (29.8%). Median survival of eligible patients was 19 weeks with mitomycin plus BTG versus 21 weeks with MeCCNU plus BTG: no difference. Median survival of responders (40 weeks) and patients with stable disease (35 weeks) was significantly better than patients with increasing disease (17 weeks): p + 0.001.

A randomized, prospective trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983. Sixty patients were stratified by site (oral cavity, 19; larynx, 14; hypopharynx, 14; oropharynx, 11; nasopharynx, one; and paranasal sinuses, one) and by stage (III, 19; IV, 41), and then randomized to receive either standard treatment (defined as preoperative irradiation followed by radical excision or irradiation alone) or adjuvant chemotherapy followed by standard treatment. An additional three patients were entered into the study, but withdrew. Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed; nonresponders received standard treatment. Response to chemotherapy was complete in five and partial (greater than 50%) in 18 patients, for an overall response rate of 85%. The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months. Survival was compared for patients in both treatment groups according to the method of Lee and Desu. Despite excellent tumor response, actuarial survival was 70% in the standard treatment group as opposed to 56% in the experimental group. It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers.

Aclacinomycin-A (ACLA-A), the new anthracycline antibiotic that produces substantially less cardiotoxicity relative to doxorubicin, was evaluated in a phase II trial for advanced large cell and adenocarcinoma of the lung patients. Twenty-three patients with measurable disease were entered into the trial and received ACLA-A in doses of a weekly infusion of 65 mg/m2 and 85 mg/m2. Eighteen patients were evaluable for response and toxicity. Two patients were evaluable for toxicity only, one died before completion of a full course of therapy, and two did not receive the drug. There were no complete or partial remissions in this study. Three patients had disease stabilization for a median of 10 weeks (range 6-17). Toxicity was mainly hematologic. Nausea and vomiting were moderate. ACLA-A, in the dose schedules used, appears to have no activity in large cell and adenocarcinoma of the lung.

Anguidine was administered on a weekly schedule to 20 patients. Gastrointestinal and neurologic toxic effects were dose-limiting for both 4- and 8-hour infusions of anguidine. Myelosuppression was infrequent and not dose-related. Recommended starting doses for weekly anguidine are 6.0 mg/m2 for patients with normal hepatic function and 3.5 mg/m2 for patients with liver dysfunction.

A Phase I trial of AT-125 was completed for the bolus dose every three week schedule. Dose limiting toxicity was primarily central nervous system (CNS) in the form of ataxia, confusion, hallucinations and dysarthria. Although this was most severe at doses of 150 mg/m2, lesser symptoms were reported at all dose levels. Nausea and vomiting were moderate to severe at higher doses. Myelosuppression did not occur. This schedule is not recommended for Phase II studies until methods are developed to reduce drug-related CNS toxicity.

Fifteen adult patients with advanced solid tumors received bruceantin at doses of 1.6-6.0 mg/m2 iv for 30 minutes/week X 4, followed by a 2-week rest. The dose-limiting toxic effect was nausea and vomiting, which was more severe in patients with hepatic metastases or liver function abnormalities. Other sporadic toxic effects included fever, chills, malaise, alopecia, hypotension, thrombocytosis, and leukocytosis. Hematologic toxicity was insignificant. The recommended starting dose for phase II studies is 5 mg/m2/week X 4, every 6 weeks, with a reduction to 3 mg/m2 for patients with hepatic metastases.

A phase I trial of chlorozotocin was completed for a weekly times four dose schedule repeated every 8 weeks. Thrombocytopenia was the acute dose limiting toxicity. Nausea and vomiting were moderate to severe and dose related. Two cases of possible drug related irreversible nephrotoxicity were seen. Transient elevations of serum creatinine and mild proteinuria were noted. Also, transient elevations in SGOT were observed. One patient with a carcinoid tumor had a 60% reduction in his 5HIAA level after one course of therapy. The recommended dose for phase II clinical studies of chlorozotocin is 40 mg/m2 IV weekly for four weeks, repeated every 8 weeks.

Twenty-one children (19 with leukemia) were given 34 courses of vindesine on a weekly or twice-weekly schedule in escalating doses. Thirty-three courses were fully or partially evaluable for response and/or toxicity. Granulocytopenia was the dose-limiting toxicity. Transient jaw, neck, or bone pain was common after each dose. Motor weakness, paresthesias, and constipation were neither frequent nor severe. In this Phase I study, vindesine had some antileukemia activity in children previously treated with vincristine and other drugs. Phase II studies are warranted and a starting does of 1.85% mg/m2 twice weekly appears tolerable.

IMPY was given to 25 patients with advanced cancer on a twice weekly schedule in escalating doses from 165 to 3000 mg/m2. Nausea, vomiting, fatigue, generalized weakness, and decreases in performance status were dose-limiting. In one patient treated at a dose of 3000 mg/m2 for three doses, hemolytic anemia resulted, with a 6-g/dl decrease in hemoglobin. No tumor regression occurred. A reasonable starting dose for phase II studies is 1200 mg/m2 twice weekly for 3 weeks, with planned rapid escalation to 1800 mg/m2 in patients tolerating the lower dose level.

Clorozotocin was evaluated in patients with advanced colorectal cancer at 225 mg/m2 every six weeks in 14 patients with no prior treatment, at 200 mg/m2 in 43 patients with normal tolerance of prior chemotherapy, and at 100 mg/m2 in 38 patients with extensive or poorly tolerated prior therapy. Median survival for the respective groups was 192, 107 and 79 days; these differences are best explained as a function of performance status. Partial response was reported for one patient, 15 had disease stabilization and two had improvement short of partial remission. Myelotoxicity was acceptable at all doses, with thrombocytopenia being dose limiting at 225 mg/m2. Four patients developed azotemia during or after chlorozotocin treatment. Chlorozotocin has minimal activity against colorectal carcinomas and no dose-response relationship is evident.

Echinomycin was administered to patients with advanced carcinoma in escalating doses ranging from 60 to 1500 micrograms/m2 given weekly by 15-minute iv infusions for four doses, with a subsequent 2-week rest period. Dose-limiting nausea, vomiting, and anorexia associated with varying degrees of renal and hepatic dysfunction proved dose-limiting at the 1500-micrograms/m2 level. Thrombocytopenia was noted in 15% of patients receiving greater than or equal to 700 micrograms/m2 and was severe in 11% without an evident dose-response relationship. Leukopenia was rare and mild when encountered. Allergic reactions were observed. Phase II trials are feasible using a dose schedule of 1200 micrograms/m2/week X 4 weeks.

A phase II evaluation of DAG in head and neck cancer patients produced one partial response and one patient with prolonged stable disease from nine fully evaluable patients with squamous carcinomas. One partial response was produced in a patient with anaplastic thyroid carcinoma. No drug deaths or life-threatening toxicity were reported. Further evaluation of DAG in thyroid tumors is warranted.

Twenty patients with advanced measurable adenocarcinoma of the lung were treated with AZQ 20 mg/m2 weekly for 4 weeks, followed by a 2-week rest. No complete or partial responses were observed. Stabilization was observed in seven individuals, lasting 6-32+ weeks, with a median of 6 weeks. Toxicity was limited to reversible myelosuppression. We conclude that AZQ administered at this dose and schedule has no significant activity against advanced adenocarcinoma of the lung.

A toxicologic evaluation of dianhydrogalactitol in man was completed for a 5- and a 10-day schedule. The maximum tolerated dose was 30 mg/m2/day for the 5-day schedule and 21 mg/m2/day for the 10-day schedule. Dose-limiting myelosuppression occurred with both schedules, with leukopenia and thrombocytopenia being observed at median Days 15 and 19 respectively for the 5-day course and median Days 22 and 26 of the 10-day course. Nausea was infrequent and mild. Responses were obtained in one patient with laryngeal carcinoma and in one patient with adenocarcinoma of the lung.

Nafazatrom was tested against a variety of human malignancies with the human tumor stem cell assay at one or more of the following concentrations: 1, 10, 25, and 100 micrograms/ml X 1 h or 0.05, 0.5, or 5 micrograms/ml by continuous exposure. Major (greater than or equal to 70%) inhibition was noted in 7/52 adenocarcinomas, in 0/9 squamous carcinomas, and 1/17 other malignancies. Intermediate levels of inhibition (50 to 69%) were noted in 7/52, 4/9, and 6/17 of these respective subtypes. No clear trend toward superiority of any dose-schedule was noted. Since nafazatrom has proven non-toxic in our nearly completed Phase I study, and since this study suggests activity against several human cancers, Phase II level testing is warranted.

Clinical and pathologic studies of three cases of drug-induced cholestatic jaundice associated with the new antineoplastic agent chlorozotocin are presented. All three patients had received intermittent treatment with high doses of chlorozotocin. The recognition of this unusual form of hepatotoxicity is important in view of the many possible causes of jaundice in cancer patients.

Quinone derivatives have shown intensive antitumor activity in a broad variety of neoplasias. Aziridinylbenzoquinone is designed to have adequate lipid solubility to attain useful drug concentrations in the central nervous system. A Phase I study of aziridinylbenzoquinone was conducted in 32 patients with advanced solid cancers. The drug was given as a slow i.v. injection on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 5 to 20 mg/sq m were studied, with 3 to 10 patients treated at each level; a total of 156 doses were administered. The major toxicity was myelosuppression with the median nadir in platelet and white blood cells occurring at Days 15 to 27 of the cycle, and first appearing at doses greater than 10 mg/sq m. Anemia was first seen at the 10-mg/sq m dose level, occurring between Days 22 and 40. Nonmyelosuppressive toxic effects included nausea and vomiting, anorexia, diarrhea, stomatitis, slight alopecia, and transient fever. The highest tolerated dose was 20 mg/sq m, the recommended dose for Phase II studies. Plasma and urine pharmacokinetics were studied in 17 patients by a high-pressure liquid chromatography method. Plasma decay curves could be fitted to a two-compartment open-system model with an overall average alpha and beta half-life values of 10.5 +/- 6.28 min and 16.90 +/- 8.63 (S.D.) hr. Aziridinylbenzoquinone levels were determined in urine samples of 12 patients, but less than 0.1% of the dose was excreted in the 0- to 4-hr sample of two patients, and none was detected in the urine of 10 patients.