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Biomedical subjects

S Wadler

Publications and source records attributed to S Wadler.

At least 73 records · Page 4Linked to original sources
PubMed1996

Mature results of a phase II trial of concomitant cisplatin/pelvic radiotherapy for locally advanced squamous cell carcinoma of the cervix.

PURPOSE: Patients with locally advanced squamous cell carcinoma of the cervix have a poor prognosis when treated by standard radiotherapy (RT) alone. Factors such as large tumor volume or nodal disease result in pelvic and distant treatment failures. Cisplatin (CDDP), a known radiosensitizer with documented activity in squamous cell carcinomas, was used in a phase II prospective study to evaluate the efficacy of combined chemo/radiotherapy in locally advanced squamous cell carcinomas of the cervix. METHOD: CDDP was administered (20 mg/m2) daily X 5 at 21-day intervals with concomitant external beam and intracavity RT. Standard RT was delivered at 1.8-2.0 Gy/day, 5 fractions per week for 5 weeks. Intracavitary cesium insertions were planned to treat point A to approximately 80 Gy. RESULTS: Fifty-nine patients were enrolled from March 1986 to July 1990. Four patients were voluntarily withdrawn, leaving 55 patients evaluable for response. Of these, 16 were Stage IB/IIA, 11 were Stage IIB, 24 were Stage III, and 4 were Stage IV. The median age of patients enrolled was 47 years (range 27-79). Median follow-up time was 65 months (range 60-113). Histopathologic confirmation of node status was available in 33 patients, of whom 45.5% (15/33) had nodal metastases. Overall response was 96% (CR = 87%, PR = 9.0%) and 3.6% had progressive disease during treatment. Forty-six patients were evaluable at 5 years for overall and disease-free survival. Calculations were based on Kaplan-Meier product limit estimates. The 5-year survival was 73% for Stage IB/IIA, 60% for Stage IIB, 67% for Stage III, and 25% for Stage IV. The disease-free survival at 5 years was 73% for Stage for IB/IIA, 50% for Stage IIB, 67% for Stage III, and 25% for Stage IV. Hematologic toxicity was severe but tolerable. No treatment-related deaths occurred. CONCLUSION: Concomitant CDDP/RT is a safe and tolerable method of treating patients with locally advanced squamous cell carcinoma of the cervix. Our data suggest a benefit in both disease-free and 5-year survival, particularly notable among patients with Stage III disease.

Adult↗
PubMed1996

Phase I trial of high-dose infusional hydroxyurea, high-dose infusional 5-fluorouracil and recombinant interferon-alpha-2a in patients with advanced malignancies.

The ribonucleotide reductase inhibitor, hydroxyurea (HU), augments the cytotoxic effects of 5-fluorouracil (5FU) in vitro; both drugs are synergistic with interferon-alpha (IFN) in vitro. The aim of this phase I study was to determine the maximal duration of HU, 4.3 g/m2, administered as a parenteral infusion in combination with 5FU, 2.6 g/m2 administered over 24 hrs each week, + IFN, 9 MU, subcutaneously three times per week. There were 26 patients enrolled and evaluable. This included 14 patients with colorectal cancer of whom 13 had been previously treated, and 12 patients with other refractory malignancies (pancreas, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and others), of whom 10 were previously untreated. The dose-limiting toxicity of this regimen was myelosuppression. This prohibited dose escalation of HU above the starting dose (24 hrs) on a 6-weeks-on, 2-weeks-off therapy schedule. When filgrastim, 480 microg, was administered subcutaneously on days 3-6, the duration of HU could be extended to 48 hrs on a 2-weeks-on, 1-week-off therapy schedule. There were two instances of fatal infection, one in a patient with a rectovaginal fistula with neutropenic sepsis and the second in a patient with non-neutropenic Clostridium septicum sepsis. All therapy was administered in the ambulatory setting. There were three responders, all among previously untreated patients. High-dose parenteral hydroxyurea, 4.3 g/m2 administered over 24 hrs, can be safely combined with high-dose weekly 5FU, 2.6 g/m2 over 24 hrs + IFN, 9 MU subcutaneously three times per week, without filgrastim in the ambulatory setting. Parenteral hydroxyurea, 4.3 g/m2 over 24 hrs daily x 2 can also be combined with high-dose 5FU + IFN, but requires the addition of filgrastim to avoid severe myelosuppression.

Adult↗
PubMed1996

Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: effects in wild-type and resistant human colon cancer cells.

The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 microM to 215 microM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 microM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65% at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90% over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.

Base Sequence↗
PubMed1996

Effect of interferon on 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks.

Interferon (IFN) augments the anabolism of 5-fluorouracil (5FU) to its active metabolite, fluorodeoxyuridylate (FdUMP), which inhibits thymidylate synthase (TS). We sought to determine whether this resulted in greater perturbations of nucleotide pools and if so, whether this was associated with an increase in cell lethality, specifically focussing on the lethal cellular lesion, DNA double strand breaks (dsb). To determine whether combination therapy with 5FU + IFN resulted in greater depletion of thymidine nucleotide pools than 5FU alone, a highly sensitive DNA polymerase assay was used. In two human colon cancer cell lines, treatment with 5FU + IFN resulted in a rapid decrease in levels of dTTP by 95%. The addition of IFN to 5FU resulted in greater depletion of dTTP levels over treatment with 5FU alone by up to fourfold, and markedly augmented the dATP/dTTP ratio. The addition of IFN to 5FU had no effect on 5FU-induced perturbations in dCTP, dGTP or dATP pools at 8 and 12 h. Measurement of DNA dsb demonstrated that treatment of HT-29 cells with 10 microM 5FU for 24 h did not increase DNA dsb versus control. The combination of 5FU + 500 U/ml IFN, however, resulted in an increased number of dsb versus both 5FU and untreated control cells (P < 0.01), equivalent to 0.74 +/- 0.12 Gy. The addition of IFN to 5FU resulted in a selective further depletion of pools of dTTP and an increase in the number of DNA dsb versus 5FU treatment alone.

Antineoplastic Agents↗
PubMed1996

Phase II trial of N-(phosphonacetyl)-L-aspartate (PALA), 5-fluorouracil and recombinant interferon-alpha-2b in patients with advanced gastric carcinoma.

The aspartate transcarbamoylase inhibitor, N-(phosphonacetyl)-L-aspartate (PALA), synergistically enhanced the cytotoxicity of a combination of 5-fluorouracil (5-FU) and interferon-alpha (IFN) against human colon cancer cell lines in vitro. To test the efficacy of this combination in the clinical setting, patients with locally advanced or advanced gastric carcinoma were treated with the combination of PALA, 5-FU and IFN (PFI). Patients were required to have biopsy-proven disease beyond the scope of surgical resection, measurable disease, no prior chemotherapy, adequate bone marrow, renal and hepatic function, to be fully ambulatory and to have given informed consent. Drug was administered as follows: PALA, 250 mg/m2, 15 min i.v. infusion, days 1, 15, 22, 29, and then weekly; 5-FU, 750 mg/m2 daily x 5 as a continuous i.v. infusion beginning day 2, then at 750 mg/m2 days 16, 23 and 30, then weekly; IFN, 9 MU subcutaneously three times per week beginning day 2. There were 22 patients enrolled. The major toxicities were fatigue and associated neurotoxicity, with acceptable gastrointestinal and haematological toxicities. There was one complete responder (5%) and 3 partial responders (14%); two of these responses were durable (> 3 years). Despite this modest clinical activity, other regimens for advanced gastric cancer such as FAMTX and ELF appear to have greater activity with comparable toxicity.

Adenocarcinoma↗
PubMed1996

Phase I/II study of PIXY321 in combination with cyclophosphamide and carboplatin in the treatment of ovarian cancer.

OBJECTIVE: Our purpose was to evaluate the safety and biologic effects of PIXY321 after chemotherapy in patients with ovarian carcinoma. STUDY DESIGN: A multicenter, nonrandomized, phase I/II study of subcutaneously administered PIXY321 after the second cycle of chemotherapy in cohorts of three or more patients at 50, 125, 250, 500, 750, or 100 micrograms/m2 per day. RESULTS: Cyclophosphamide (600 mg/m2) and carboplatin (400 mg/m2) were administered every 28 days to 34 patients. At doses > or = 500 mg/m2 per day, the median nadir platelet and median nadir absolute neutrophil counts in cycle 2 (with PIXY321) compared with cycle 1 (control) were both higher in 13 of 26 (50%) patients. Twenty-one patients were withdrawn from the study. A total of 17 of 21 (81%) were removed for myelosuppression (n = 15) or PIXY321 toxicity (n = 2). A total of 28 of 34 (82%) patients had injection site reactions. Thirty-seven nonhematologic grade 3 events occurred. CONCLUSIONS: At these doses and schedules PIXY321 can be safely administered. Aggressive dosing of cyclophosphamide and carboplatin could not be maintained for six cycles in the majority (62%) of patients.

Adult↗
PubMed1996

Phase II trial of prolonged continuous infusion of 5-fluorouracil and interferon-alpha in patients with advanced pancreatic cancer. Eastern Cooperative Oncology Group Protocol 3292.

Evidence suggests that interferon-alpha (IFN-alpha) augments the antineoplastic activity of 5-fluorouracil (5-FU) in human adenocarcinoma cell lines in vitro and may enhance the efficacy of 5-FU in patients with advanced colorectal carcinoma. In addition, 5-FU may be more effective when given as a prolonged, continuous i.v. infusion (PCI). The Eastern Cooperative Oncology Group performed a Phase II trial of PCI 5-FU plus IFN-alpha in patients with advanced pancreatic carcinoma. Twenty-six patients with advanced, surgically incurable adenocarcinoma of the pancreas received PCI 5-FU (250 mg/m2 daily for 28 days) in combination with IFN-alpha (5 x 10(6) IU/m2 s.c. thrice weekly). Treatment cycles were repeated 14 days or longer after completion of the previous cycle. Treatment was interrupted prior to day 28 if intolerable toxicity developed, and the dose of 5-FU was reduced in subsequent cycles. Partial response occurred in two of 24 evaluable patients (8%; 95% confidence interval, 0-19%). The majority of the study group (88%) had liver metastases. Patients whose serum lactate dehydrogenase (LDH) was more than twofold elevated developed 5-FU-related toxicity significantly sooner than patients with smaller elevations in serum LDH (9 vs. 22 days; p = 0.003). A similar trend was observed for patients with a more than twofold elevation in serum glutamic-oxaloacetic transaminase (SGOT; 9 vs. 15 days; p = 0.07). In conclusion, PCI 5-FU plus IFN-alpha has minimal activity in patients with advanced pancreatic carcinoma, and elevated serum LDH and/or SGOT may be useful for predicting greater toxicity from 5-FU-based therapy in patients with liver metastases.

Adenocarcinoma↗
PubMed1996

The potential role of amifostine in conjunction with cisplatin in the treatment of locally advanced carcinoma of the cervix.

The treatment of locally advanced carcinoma of the cervix with radiation therapy as a single modality is inadequate, specifically for stage III and IVA disease. While chemotherapy as single-modality therapy is ineffective in advanced cervical cancer, there is some evidence of efficacy when used in combination with radiation therapy. A recently conducted phase II trial from the Albert Einstein College of Medicine used standard whole pelvic radiation therapy with concurrent cisplatin 20 mg/m(2)/d X 5 days for four courses in women with stage IB to IVA cervical cancer. Toxicities, mainly hematologic and soft tissue, were acceptable in this trial. There was only a modest impact on disease-free survival among women with stage III disease. A subsequent phase I trial conducted by the New York Gynecologic Oncology Group tested the addition of amifostine to the combination of cisplatin plus radiation therapy using the Albert Einstein College of Medicine regimen. Amifostine at doses escalated from 340 to 910 mg/m(2) was administered immediately before cisplatin. The dose-limiting toxicity was hypotension. Amifostine should be tested in future clinical trials either as a cytoprotective agent in patients receiving cisplatin plus radiation therapy or, alternatively, to assess dose intensification of cisplatin in combination with radiation therapy.

Amifostine↗
PubMed1995

5-Ethoxy-2'-deoxyuridine, a novel substrate for thymidine phosphorylase, potentiates the antitumor activity of 5-fluorouracil when used in combination with interferon, an inducer of thymidine phosphorylase expression.

Clinical studies have demonstrated that the combination of 5-fluorouracil (FUra) and IFN-alpha has activity in the treatment of advanced colorectal cancer. Treatment of human colon carcinoma cells with IFN caused a 5-fold increase in the level of thymidine phosphorylase (TP) mRNA and an 8-fold increase in TP enzyme activity. Since TP catalyzes the first step in the direct conversion of FUra to deoxyribonucleotides, its induction by IFN is a potential biochemical mechanism for the modulation of the antitumor activity of FUra. In contrast to the activity measured in cell extracts, however, thymine utilization by intact cells was increased less than 2-fold by IFN, suggesting that the metabolic activation of FUra by TP in the IFN-treated cells was similarly suboptimal. This was likely due to a rate-limiting amount of cosubstrate for TP, and in this study, a series of 5-substituted 2'-deoxyuridine analogues were synthesized and tested as potential deoxyribose donors for TP. One of the compounds, the novel pyrimidine analogue 5-ethoxy-2'-deoxyuridine (EOdU), was found to be a substrate for the transferase reaction of TP, to have little or no direct cytotoxicity, to selectively increase the cellular levels of 5-fluoro-dUMP, to enhance the inhibitory effect of FUra on thymidylate synthase activity, and to potentiate the cytotoxicity of FUra and IFN in human colon carcinoma cells. EOdU was tested in vivo against HT-29 cells grown as xenografts in nude mice. The combination of EOdU+FUra+IFN-alpha 2a produced tumor regressions and a significantly greater delay in tumor growth when compared to FUra+IFN-alpha 2a, FUra+EOdU, or FUra or IFN used alone; tumors were 72% smaller in the EOdU+FUra+IFN-alpha 2a-treated animals compared to the saline control group. A comparable antitumor effect was also found when a related nucleoside analogue, 5-propynyloxy-2'-deoxyuridine, was used with FUra+IFN, and it also showed modulating activity when used with only FUra. The antitumor activity of the three agent combination (nucleoside+IFN+FUra) was comparable to that of a higher dose of FUra used alone, but it was substantially less toxic to the animals than the higher dose of FUra, indicating that the modulating agents improved the therapeutic index of FUra.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil.

Interferon-alpha (IFN alpha) potentiates the antitumor activity of 5-fluorouracil (FUra) in colon cancer in vitro, in vivo, and clinically. A likely mechanism for this action is the induction by IFN alpha of thymidine phosphorylase (TP), the first enzyme in one pathway for the metabolic activation of FUra to fluorodeoxyribonucleotides. To test this hypothesis, an expression vector containing the TP cDNA was transfected into HT-29 human colon carcinoma cells. Five stable transfectants were selected and analyzed. All showed increased sensitivity to FUra cytotoxicity, ranging from a 2-fold to a 19-fold decrease in the IC50 for FUra, compared to wild-type cells. Levels of TP mRNA, protein, and enzyme activity were elevated in the transfectants, and there was a significant correlation between the relative increase in sensitivity to FUra and both the increase in both TP mRNA levels and TP activity. Transfected cells exhibited increased formation of FdUMP, but not the ribonucleotides FUDP and FUTP, from FUra when compared to wild-type cells. The changes in TP activity, FdUMP formation, and FUra sensitivity in the transfected cells were comparable with those seen after treatment of wild-type cells with IFN alpha. These studies provide direct evidence for the role of TP in mediating the sensitivity of colon carcinoma cells to FUra, and further support the importance of the induction of TP in the biomodulating action of IFN alpha on FUra chemosensitivity.

Colonic Neoplasms↗
PubMed1995

A phase I trial of cyclosphosphamide and carboplatinum combined with interleukin-3 in women with advanced-stage ovarian cancer.

The hematopoietic growth factor, recombinant human interleukin-3 (rhu IL-3), stimulates production of both leukocytes and platelets, and thus potentially has greater utility than growth factors that solely stimulate leukocytes production when employed with dose-intensive chemotherapeutic regimens. To determine the optimal schedule for administration of rhu IL-3 in combination with cyclophosphamide and carboplatin, an aggressive regimen for the treatment of advanced ovarian cancer, a phase I trial was initiated by the New York Gynecologic Oncology Group. Following surgical debulking, all patients received cyclophosphamide and carboplatin for 6 cycles. rhu IL-3 was administered at 50, 250, or 500 microgram subcutaneously for 5 days either immediately prior to or after administration of chemotherapy. Cohorts of six patients were treated at each dose level (three pre- and three postchemotherapy). Eighteen patients received 91 cycles of treatment. The major toxicities attributable to rhu IL-3 included fevers, chills, malaise, nausea, and headache, but were not dose-limiting at the doses of rhu IL-3 employed. The major finding of this study was that rhu IL-3 administered after chemotherapy offered greater platelet protection than rhu IL-3 administered prior to chemotherapy as assessed by median platelet nadir and duration of platelet counts < 50,000/mm3. A second major finding was a dose-response relationship for rhu IL-3: the two higher doses employed, 250 and 500 micrograms, offered more effective platelet protection than the lower dose employed, 50 micrograms. rhu IL-3 had no significant effects on leukocyte nadirs or duration of nadirs at any schedule or dose employed. rhu IL-3 may reduced the thrombocytopenia associated with aggressive treatment with cyclophosphamide and carboplatin, although this remains to be confirmed in a randomized, placebo-controlled trial. The effects of rhu IL-3 are dose- and schedule-dependent.

Adult↗
PubMed1995

Biochemical modulation of cytotoxic drugs by cytokines: molecular mechanisms in experimental oncology.

The combination of cytokines and cytotoxic drugs offers a new approach to increase the therapeutic index in the treatment of neoplastic diseases. There is no consensus on optimal strategies for combining these agents so far. The molecular mechanisms underlying the interaction, however, should be defined in order to design clinical trials based on preclinical rationales. The broad spectrum of cytotoxic drugs whose activity can be enhanced by cytokines argues for multiple levels of drug interaction in vitro: alteration in the cellular drug uptake, modulation of drug target enzymes, and changes in metabolism or disposition of a drug. In vivo interaction between cytokines and cytotoxic agents involves an additional layer of complexity because of the effects of cytokines on the host immune system and on drug-metabolizing enzymes. A major mechanism involved in the synergistic interaction of interferon (IFN) and 5-fluorouracil (5-FU) seems to be the increase of active 5-FU metabolites by IFN. Moreover, IFN can reverse resistance against 5-FU by inhibiting the overexpression of thymidylate synthase. The absence of cytokinetic effects of IFN and FU argues against the recruitment of Gs cells into the cell cycle. Topoisomerase has emerged as a critical intracellular target of cytotoxic drugs. There is convincing evidence that the synergy between tumor necrosis factor (TNF) and topoisomerase-targeted intercalative (Adriamycin, doxorubicin hydrochloride; m-AMSA, amsacrine; mitoxantrone) and nonintercalative (VM-16, etoposide; VM-26, teniposide) drugs is related to a rapid increase in specific activity of topoisomerase I and II, resulting in enhanced DNA strand breaks and cleavage complex. Furthermore, sensitivity to topoisomerase II targeted drugs can be enhanced by granulocyte colony-stimulating factor (G-CSF) through elevated enzyme activity in tumor cell response to G-CSF. The synergistic interaction between cytokines and cytotoxic agents seems to be sequence dependent. It has recently been demonstrated that newly synthesized metal compounds and IFN are synergistic only after preincubation with cytokines. Cytokines can modulate expression of adhesion receptors on tumor cell lines, thereby influencing their metastatic potential. A considerable number of phase II trials with combination of cytokines and cytotoxic drugs based on these mechanisms have demonstrated promising response rates and tolerable toxicity. Phase III trials are currently in progress to identify enhanced activity combining cytokines and cytotoxic drugs in the treatment of malignancies.

Animals↗
PubMed1995

Phase II trial of chemotherapy, external and intraluminal radiation plus surgery for oesophageal cancer.

A pilot study was performed to assess the feasibility of combining 5-fluorouracil, recombinant alpha-2b-interferon, external radiation therapy and intraluminal high dose rate brachytherapy with surgery in patients with locally advanced esophageal carcinoma. 5-fluorouracil, 750 mg m-2, was administered via continuous 5-day infusion beginning day 1 and weekly thereafter; interferon, 10 mu subcutaneously, was administered three times per week beginning day 1 and sargramostin, 5 micrograms kg-1, was administered on days without 5-fluorouracil. External radiation began on day one using 1.5 daily fractions to 55.5 Gy. Intraluminal brachytherapy was delivered concomitantly once each week for 5 fractions of 4 Gy. None of the first eight patients went to surgery. The external radiation was changed to 1.5 Gy BID to 45 Gy followed by BID intraluminal radiation to 15 Gy. Of the last four patients, there was one case of radiation myelitis. It was found that successful surgery was not possible and excessive toxicities, including radiation myelitis, occurred with this aggressive regimen.

Aged↗