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S Wadler

Publications and source records attributed to S Wadler.

At least 109 records · Page 6Linked to original sources
PubMed1993

Clinical and pharmacological studies of interferon and chemotherapy in gastrointestinal and breast cancer.

The interferons enhance the cytotoxicity of antimetabolites, alkylating agents, and plant antibiotics against cultured human tumours in vitro and in vivo. Five clinical trials in humans with advanced colorectal carcinoma have demonstrated responses ranging from 26 to 63% in patients treated with 5-fluorouracil (5-FU) plus interferon-alpha (IFN-alpha), suggesting improved response with the combination as compared with 5-FU alone. In addition, responses have been observed in patients with adenocarcinomas of the lung, pancreas, breast, and kidney, squamous cell carcinoma of the oesophagus, and urothelial carcinoma treated with 5-FU/IFN-alpha. However, enhanced 5-FU-related toxicity was observed in these studies, as has been observed when 5-FU is combined with other modulating agents, such as leucovorin. While some studies suggested that enhanced 5-FU-related toxicity was associated with an IFN-alpha-induced reduction in 5-FU clearance when 5-FU was given as an intravenous (i.v.) bolus (750 mg/m2 IV weekly) or as a high-dose five-day continuous infusion (CI) (750 mg/m2/day x 5 days), another study found enhanced 5-FU toxicity in the absence of pharmacokinetic perturbation when 5-FU was given as a low-dose prolonged CI (300 mg/m2/day x 28 or more days).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

The role of interferons in the treatment of solid tumors.

BACKGROUND: Originally described as antiviral agents, interferons (IFN) were investigated as potential anticancer agents because of their antiproliferative and cytotoxic effects, their ability to activate specific components of the immune system, and their relatively modest toxicities. Interest intensified when durable complete remissions were observed in patients with hairy cell leukemia after IFN treatment; modest, but reproducible activity also was found against tumors such as melanoma and renal cell carcinoma which are unresponsive to conventional chemotherapy. Observations of synergy between IFN and cytotoxic drugs in vitro and in vivo suggested that IFN may have additional utility as modulating agents. METHODS: Reports of major clinical trials using IFN either alone or in combination with other agents were reviewed. Activity was identified by disease site. Correlations were made with important preclinical studies. RESULTS: IFN has reproducible, but modest, single-agent activity against melanoma, renal cell carcinoma, and acquired immune deficiency syndrome-related Kaposi sarcoma. IFN may be useful in the treatment of a number of benign, in situ, or low-grade tumors. IFN in combinations with cytotoxic agents have demonstrated activity in solid tumors. Clinical trials using combinations of IFN and 5-fluorouracil or dacarbazine suggested a potential benefit for the combination compared with single-agent chemotherapy. These are preliminary findings that require confirmation, but they suggest that combination therapy should be investigated further. In early preclinical and clinical studies, combinations of IFN and other biologic agents, hormonal agents, and radiation therapy appear to be interesting. CONCLUSIONS: The role of IFN in the treatment of solid tumors may be evolving from that of single-agent therapy to combination therapy with other active agents. Additional studies are required to determine the optimal doses, schedules, and sequencing of these combination therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

High-dose local irradiation plus prophylactic hepatic irradiation and chemotherapy for inoperable adenocarcinoma of the pancreas. A preliminary report of a multi-institutional trial (Radiation Therapy Oncology Group Protocol 8801).

Adenocarcinoma of the pancreas is an extremely malignant neoplasm with a particular propensity to spread to the liver. In an effort to combine chemotherapy with high-dose local irradiation plus a modest dose of irradiation to suspected (subclinical) hepatic metastasis, patients with unresectable pancreatic carcinomas with no known distant metastasis were treated on a prospective multi-institutional Radiation Therapy Oncology Group (RTOG) Phase I/II trial. High total dose continuous radiation therapy to the pancreas (6120 cGy in 34 fractions over 7 weeks) and simultaneous prophylactic hepatic irradiation (PHI, 2340 cGy in 13 fractions for the last 2.5 weeks) were combined with administration of 5-fluorouracil 1000 mg/m2/day (maximum, 1500 mg) by intravenous continuous infusion for 5 days starting on day 1 and repeated on day 30 for 5 days, followed by a dose of 600 mg/m2 as a weekly bolus injection starting during week 9 for 6 months. In 18 months, 81 patients were enrolled in the study; 79 were evaluable with a minimum potential follow-up of 8.2 months. The patients ranged in age from 32 to 75 years (median, 64 years). Karnofsky performance status was 80 to 100 in 74% of patients. The tumor was confined to the head of the pancreas in 72% of patients. The planned radiation therapy for the pancreas was completed in 87% of patients, 80% received the planned PHI, and 85% completed the first two cycles of chemotherapy. Seventy-five percent of patients completed both treatments according to the protocol. Most patients who did not complete both treatments had tumor progression or refused additional therapy. During all cycles of chemotherapy and radiation therapy, 2 patients died of complications (Grade 5, 1 hepatic and 1 infection), 9 had life-threatening reactions (Grade 4, 7 hematologic, 1 neurologic, and 1 mucositis), and 31 patients had severe effects (Grade 3) according to the RTOG toxicity scale. Overall hepatic metastasis was documented in 32% (13% as the first site of failure), persistent or progressive pancreatic tumor was evident in 73%, and abdominal and extra-abdominal spread were reported in 27% and 8% of patients, respectively. Eighty percent (63 patients) died (median survival, 8.4 months). Although this study suggests that PHI may reduce the frequency of hepatic metastasis, failure to control the primary tumor and intraabdominal spread remain overwhelming.

Adenocarcinoma↗
PubMed1992

Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells.

Interferon-alpha (IFN alpha) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFN alpha treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFN alpha produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFN alpha did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFN alpha also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFN alpha on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.

Adenosine↗
PubMed1992

Antineoplastic activity of the combination of 5-fluorouracil and interferon: preclinical and clinical results.

Interferon (IFN) is capable of modulating the cytotoxic effects and clinical activity of the fluorinated pyrimidine, 5-fluorouracil (5-FU). This occurs in the absence of a demonstrable effect on immune function, suggesting that these effects occur at the biochemical level. Pharmacokinetic studies have also demonstrated that IFN can increase serum levels of 5-FU. The relative importance of these effects on enhancement of 5-FU activity remains to be investigated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Principles in the biomodulation of cytotoxic drugs by interferons.

The interferons (IFNs) were identified as novel, endogenous antiviral agents in 1957. Shortly thereafter, antiproliferative and immunostimulatory activities were identified for these compounds. Based on these observations, partially purified IFNs entered clinical trials in the 1970s and recombinant IFNs in 1980. IFNs have demonstrated important clinical activity in hairy cell leukemia, melanoma, renal cell carcinoma, and Kaposi's sarcoma as monotherapy. Shortly after their introduction into clinical trials, however, preclinical studies demonstrated synergistic interactions between IFNs and cytotoxic drugs. Numerous preclinical trials have demonstrated a broad spectrum of interactions between IFNs and at least 20 cytotoxic agents both in vitro and in vivo. Early clinical trials suggest a benefit to combinations of fluorouracil and recombinant interferon alfa in refractory gastrointestinal malignancies. Combinations of IFNs and cytotoxic agents deserve further investigations; however, different principles apply for combining IFNs with cytotoxic drugs than for the design of combination chemotherapy regimens.

Antineoplastic Agents↗
PubMed1991

Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern Cooperative Oncology Group study.

In a pilot clinical trial, treatment of patients with advanced colorectal carcinoma with the combination of fluorouracil (5FU) and recombinant interferon alfa-2a (IFN) resulted in objective tumor regression in 62% of patients. To confirm these findings in a multiinstitutional setting, a phase II clinical trial was initiated by the Eastern Cooperative Oncology Group (ECOG) in 1989. The treatment regimen was identical to that used in the earlier study: 5FU 750 mg/m2/d for 5 days as a continuous infusion followed by weekly outpatient bolus therapy and IFN 9MU subcutaneously beginning day 1 and administered three times per week. Doses were modified for gastrointestinal, hematologic, and neurologic toxicity and for fatigue, similarly to those used in the previous pilot trial. Thirty-eight patients were registered; 36 are evaluable for response (one lost to follow-up and one with nonmeasurable disease). All patients had metastatic or locally recurrent disease beyond the scope of resection; 31 of 38 had liver metastases, and 20 of 38 had two or more sites of involvement. Eight patients had grade 4 toxicities, including sepsis (nonneutropenic) (one), watery diarrhea (two), and granulocytopenia (six). Grade 3 neurologic toxicities were observed in two (5%) patients and included slurred speech and gait disturbance. Objective response was 42% (95% confidence interval [Cl], 27% to 58%), including one clinical complete responder and 14 partial responders. Among the responding patients, the median time to treatment failure was 8 months. Two patients remain on treatment at 10+ and 16+ months: median survival has not been reached. The results of this multiinstitutional trial suggest that the addition of IFN to 5FU enhances the objective response rates achieved in patients with advanced colorectal carcinoma and that the toxicities of this regimen are acceptable.

Adult↗
PubMed1991

Reversal of doxorubicin resistance by hydrophobic, but not hydrophilic, forskolins.

The plant diterpene forskolin reverses acquired resistance to doxorubicin in variants of the murine sarcoma S180 cell line. Because forskolin is known to elevate intracellular cAMP levels, investigations were performed to determine whether this reversal of resistance resulted from effects on signal transduction. Two analogues of forskolin, dideoxyforskolin, which does not elevate cAMP, and a water-soluble analogue, were also investigated. Although all three diterpenes elevated levels of either cAMP or protein kinase C, these effects were not consistently associated with reversal of doxorubicin resistance. Likewise, all three diterpenes were capable of displacing [3H]azidopine from P-glycoprotein, but reversal of doxorubicin resistance was observed only with forskolin and dideoxyforskolin, suggesting that binding to P-glycoprotein may be a necessary, but not sufficient, condition for reversing doxorubicin resistance. The hydrophobicity of the compounds appeared to be the single factor most consistently related to reversal of doxorubicin resistance in this cell system, with the hydrophilic compound water-soluble forskolin failing to produce this result, even at concentrations 10-fold higher than effective concentrations of the hydrophobic diterpenes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

The role of immunotherapy in colorectal cancer.

Despite landmark advances in the molecular biology and surgical adjuvant therapy of colorectal cancer in the past decade, this illness remains a significant health hazard. Conventional therapies, including surgery, radiation therapy, and chemotherapy, have had limited utility and have often resulted in unacceptable host toxicities. Therapies dependent on potentiation of the host immune response are attractive alternatives to conventional treatment because of their greater specificity and diminished toxicity. Furthermore, the efficacy of many of these therapies has been demonstrated in preclinical models, which is important given the relative refractoriness of colorectal cancer to chemotherapy. Both active specific therapies, such as tumor vaccines, and passive therapies, such as monoclonal antibodies, have been investigated. In early clinical trials, both have demonstrated modest activity. Nonspecific immune stimulation with agents such as bacillus Calmette-Guérin or methanol extraction residue appear to have little utility, but with the development of recombinant DNA technology, specific cytokines with more precisely identified targets have been synthesized in sufficient quantities for clinical trials. Finally, combinations of biologics or combinations of biologics with conventional therapies, such as fluorouracil (5-FU)/levamisole and 5-FU/interferon, have been investigated and appear to be useful in the treatment of surgically resected and advanced colorectal carcinoma, respectively. The utility of these therapies is hampered by a limited understanding of their precise mechanisms of action and optimal conditions for administration. Nevertheless, immunotherapy of colorectal carcinoma remains an important and promising area for further clinical investigation.

Antibodies, Monoclonal↗
PubMed1990

Interaction of fluorouracil and interferon in human colon cancer cell lines: cytotoxic and cytokinetic effects.

Fluorouracil (FUra) is the most active agent in advanced colorectal carcinoma, and this activity can be enhanced by various modulating agents both in vitro and in vivo. To determine whether interferon (IFN) is capable of augmenting the cytotoxic and cytokinetic effects of FUra, combinations of FUra and IFN alpha, -beta, and -gamma were tested against 2 human colon cancer cell lines in vitro. In a clonogenic assay, IFN alpha and -beta, at concentrations that produced less than 1 log cell kill, significantly increased the cytotoxic effects of FUra in both cell lines. IFN gamma also enhanced the cytotoxic effects of FUra, but unlike IFN alpha and -beta, only at the highest concentrations tested. Median effects analysis demonstrated that all 3 IFNs exhibited synergy with FUra. Combinations of IFNs were no more effective at modulating FUra activity than single agent IFN. Flow cytometric studies indicated that these effects did not correlate with cytokinetic alterations. Only the combination of FUra and IFN beta produced cytokinetic effects different from those of FUra alone. Incubation with IFN alpha or IFN gamma for 24 h resulted in only modest cytokinetic alterations, and they did not modify the effects of FUra. These results indicate that IFN is capable of increasing the cytotoxic actions of FUra and that this is separable from any cytokinetic effects produced by the interferons.

Cell Cycle↗
PubMed1990

Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review.

The combination of interferon (IFN) and conventional chemotherapeutic agents offers a promising therapeutic approach for the treatment of cancer. However, there is as yet no consensus on optimal strategies for combining this family of compounds with other cancer therapies. While in vitro studies have demonstrated both direct cytotoxic and cytokinetic effects for IFN, a more interesting role derives from its ability to synergistically potentiate the activity of a wide variety of cytotoxic agents against multiple human and rodent tumors, both in vitro and in animal models. The interaction between IFN and cytotoxic agents in vitro is complex and depends not only on the choice of cytotoxic agent but also on the concentrations, ratios, duration, and sequence of exposure to the two drugs. Preliminary data suggest that some combinations are not merely additive but rather that IFN may biochemically modulate the cellular uptake or metabolism of the cytotoxic agent resulting in synergistic antineoplastic activity. In vivo interactions between IFN and cytotoxic agents involve an additional layer of complexity because of the potential effects of the biological agent on the host immune system and drug-metabolizing enzymes. Furthermore, IFN may have a protective effect on normal host tissues which theoretically could allow for the delivery of higher doses of cytotoxic agents. The results of early clinical trials using combinations of IFN with chemotherapeutic agents have generally been disappointing. This may be due to the inability of preclinical models to accurately predict the clinical situation or alternatively from a failure to incorporate information on dose, scheduling, and sequence of drug administration into clinical trials. Preliminary clinical studies with IFN-alpha and the fluorinated pyrimidine, 5-fluorouracil, in patients with advanced colorectal carcinoma suggest that IFN may enhance the effects of the antimetabolite. Confirmatory trials are in progress. Further trials designed to exploit the preclinical experience with combinations of IFN and cytotoxic agents are warranted.

Animals↗
PubMed1990

Phase I trial of 5-fluorouracil and recombinant alpha 2a-interferon in patients with advanced colorectal carcinoma.

We have previously shown that the combination of 5-fluorouracil (5-FUra) and recombinant alpha-2a-interferon (rIFN-alpha-2a) produced objective responses in 23 of 32 (63%) previously untreated patients with advanced colorectal carcinoma. Because in vitro data suggest that rIFN-alpha-2a modulates the cytotoxic effects of 5FUra in a concentration-dependent manner, a phase I clinical trial was initiated to determine the maximum tolerated dose of rIFN-alpha 2a when administered in combination with 5FUra. A total of 27 patients with advanced colorectal carcinoma were enrolled. The median age was 64 years, and the median performance status was 1. A total of 18 patients had no prior chemotherapy and 19 no prior 5FUra. 5FUra was administered at 750 mg/m2/day by continuous i.v. infusion for 5 days, followed by weekly bolus therapy. rIFN-alpha 2a was administered at 6, 9, 12, 15, or 18 x 10(6) units s.c. beginning on day 1. The dose-limiting toxicity of this regimen was fatigue, resulting in a decrease in performance status, and this was the only toxicity that correlated with increasing dose of rIFN-alpha 2a. Eastern Cooperative Oncology Group grade 3-4 toxicities included leukopenia (6), thrombocytopenia (2), anemia (4), stomatitis (4), diarrhea (4), neurological (2), infection (2), and allergy (2). Three quarters of the patients required interruption of therapy or dose reductions of either 5FUra or rIFN-alpha 2a for toxicity. Among the patients with measurable disease who were previously untreated with 5FUra, 5 of 9 at the lowest dose levels achieved an objective response, including one pathological complete responder, whereas 0 of 9 at the three highest dose levels responded. Among patients previously treated with 5FUra, only 1 achieved an objective response. We conclude that the maximum tolerated dose of rIFN-alpha 2a, when administered with 5FUra as above, is 15-18 x 10(6) units; however, the efficacy of this regimen does not appear to be related to the dose intensity of rIFN-alpha 2a, and future regimens should employ a lower dose, intermittent schedule of rIFN-alpha 2a, which may be better tolerated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Abnormal cervical cytology leading to the diagnosis of gastric cancer.

There have been nine cases reported in the English literature in which the finding of malignant cells on cervical/vaginal cytology led to the diagnosis of primary gastric cancer. We report on a patient with gastric carcinoma, metastatic to the cervix, in which the diagnosis was suspected by the finding of signet ring cells on a Papanicolaou smear of the cervix. Prior to treatment of this patient, concordance of signet ring carcinoma on cervical and ascitic fluid cytology and on cervical and gastric biopsies was documented; this has not been reported previously. Thirty-four additional cases of gastric carcinoma metastatic to the cervix are reviewed. This paper is presented to remind the clinician that, however rare, metastases from the gastrointestinal tract to the uterine cervix do occur.

Adenocarcinoma, Mucinous↗