Biomedical subjects

D L Trump

Publications and source records attributed to D L Trump.

At least 37 records · Page 2Linked to original sources

PubMed1997

Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system.

In a murine squamous cell carcinoma (SCC) model, we have demonstrated that both 1,25-dihydroxycholecalciferol (1,25-D3) and the analogue 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (Ro23-7553) have significant in vitro and in vivo antitumor activity. We have examined here the cell cycle effect of 1,25-D3 and Ro23-7553 on SCCVII/SF tumor cells by quantitating nuclear DNA using a detergent-trypsin method via flow cytometry analysis. Both 1,25-D3 and Ro23-7553 resulted in a significant increase of cells in G0-G1, with an accompanying decrease of cells in S phase. The ability to arrest cells in G0-G1 has been exploited by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diamminodichloroplatinum; cDDP). Using the in vitro clonogenic assay, pretreatment with Ro23-7553 for 24-48 h significantly enhanced cDDP-mediated tumor cell kill as compared to concurrent treatment with Ro23-7553 and cDDP or cDDP alone. To examine the effect of Ro23-7553 and cDDP in vivo, C3H/HeJ mice with 9-14-day SCC tumors were treated either for 3 days with varying i.p. doses of Ro23-7553 or for 7 days continuously through the use of Alzet pumps, and on the last day of Ro23-7553 treatment, cDDP (1-6 mg/kg) was administered. Using the in vivo excision tumor cell clonogenic assay, in which tumors were removed from animals 24 h after cDDP treatment and plated in a clonogenic assay, pretreatment with Ro23-7553 markedly enhanced cDDP-mediated clonogenic tumor cell kill, even at low doses of cDDP as compared to cDDP treatment alone. Similarly, a significant decrease in fractional tumor volume and increase in tumor regrowth delay was observed when animals were pretreated before cDDP with Ro23-7553 as compared to either agent alone. These results demonstrate a significant enhanced antitumor effect with Ro23-7553 pretreatment before cDDP both in vitro and in vivo and suggest that Ro23-7553 may potentiate cDDP cytotoxicity through effects on cell cycle progression.

Animals↗

PubMed1997

Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity.

Interleukin-1alpha (IL-1alpha) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated antitumor responses. Studies were undertaken to examine the ability of IL-1alpha to enhance the activity of cyclophosphamide (CTX) administered in combination with carboplatin. To determine the in vivo effect of IL-1alpha, CTX and/or carboplatin, mice bearing 14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5-150 mg/kg), human IL-1alpha (125 microg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell assay. Even at the lowest doses of CTX, IL-1alpha significantly enhanced the clonogenic tumor cell kill when compared to treatment with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1alpha or CTX/carboplatin). Significant enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1alpha. The interaction between the three-drug combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for IL-1alpha and CTX when used in this combination. These results demonstrate that IL-1alpha can synergistically enhance the antitumor efficacy of CTX and the combination of CTX and carboplatin.

Animals↗

PubMed1997

A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.

Adult↗

PubMed1997

Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system.

OBJECTIVES: Risk factors for prostate cancer (PCa)-related mortality include old age, black race, and residence in northern latitudes. The objectives of this study are to examine the in vitro and in vivo effects of 1,25-dihydroxycholecalciferol (1,25-D3) and less-hypercalcemic analogues on the Dunning rat prostate adenocarcinoma model. METHODS: To evaluate the effect of 1,25-D3 on PCa in vitro, we used the highly metastatic Mat-lylu (MLL) and moderately metastatic R3327-AT-2 (AT-2) Dunning prostate cell lines, and examined effects on growth, clonogenicity, differentiation, and cell cycle. In vivo analysis included examination of the effects of these compounds on tumor growth and metastasis. RESULTS: Using both the 3-day MTT and 7-day clonogenic assay, 1,25-D3 demonstrated a growth inhibitory effect with a concentration for 50% inhibition (IC50) of approximately 20 microM for both MLL and AT-2. Cell cycle analysis of treated MLL cells (10 microM 1,25-D3 for 48 hours) had 25% more cells in the G0/G1 phase than did control cells. To examine the in vivo effect of 1,25-D3 and the less hypercalcemic vitamin D analogue, Ro25-6760 (or 6760), on MLL PCa growth and metastasis, tumors (5 x 10(5) cells) were implanted subcutaneously into the flank of Copenhagen rats on the same day that treatment was initiated with 1,25-D3 (1 microgram) or 6760 (1 or 5 micrograms); rats received treatment three times a week. After 3 weeks, 1,25-D3 and 6760 (5 micrograms dosing) resulted in an inhibition of tumor volume and a reduction in the number and size of lung metastases. CONCLUSIONS: These preclinical studies demonstrate the profound in vitro, or in vivo, or both antiproliferative and differentiating effects of 1,25-D3 and 6760 on PCa and suggest that these drugs may have potential beneficial effects in the treatment of advanced PCa.

Adenocarcinoma↗

PubMed1997

Megestrol acetate in the treatment of hormone refractory prostate cancer.

This retrospective study evaluates the efficacy of megestrol acetate in patients with hormone refractory metastatic adenocarcinoma of the prostate. Data are presented from 14 patients with advanced prostatic adenocarcinoma who were treated with 160-320 mg of megestrol acetate daily. Each patient was either asymptomatic or had minimal cancer-related symptoms. Disease response was monitored by prostate-specific antigen levels. The response rate was 14%, with two patients having a partial response. No complete responses were observed. The median time to disease progression was 2 months. Our findings when considered together with results from previously published data demonstrate little activity of megestrol acetate in patients with hormone refractory prostate cancer. Therefore, we cannot recommend megestrol acetate as an effective second-line therapy.

Adenocarcinoma↗

PubMed1997

Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study.

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is a disease known to demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to reverse multidrug resistance in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma. Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for 5 days); patients with stable or progressive disease were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day for 13 days). Sixty-three patients were randomized to each arm. Eighty patients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclosporine A. No responses were observed, although four patients with progressive disease on prior vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed. Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other responses were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However, 9% of patients developed transient ataxia with or without neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis. We conclude that advanced renal cell carcinoma is a highly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the design and conduct of this study.

Adult↗

PubMed1996

Glutathione and glutathione S-transferase in benign and malignant prostate cell lines and prostate tissues.

Metastatic prostate adenocarcinoma is unresponsive to alkylator chemotherapy with virtually no prolonged remissions. Glutathione (GSH) and glutathione S-transferase (GST) have been reported to play a role in tumor resistance to alkylator therapy; however, there are no baseline studies that have investigated and compared GSH and GST in human prostate cell lines and tissues. Thus, we determined the GSH content and GST activity in benign prostate, in primary and metastatic prostate adenocarcinoma tissues, in immortal adenocarcinoma cell lines, and in primary cell cultures derived from both benign prostate and primary prostatic carcinoma tissue. The GSH content was higher in the immortal cell lines than in the fresh tissues and primary cultures. Conversely, the GST activity was significantly higher in the tissues and primary cultures than in the cell lines. The GSH content and GST activity of the primary cultured prostatic cells were similar to those of the prostate tissues. The differences between the immortal prostate cancer cell lines and prostate tissue are of sufficient magnitude to suggest that in vitro results with cell lines may not extrapolate to prostate cancer in vivo. The GSH content and GST activity in a prostate specific antigen-secreting human prostate tumor xenograft, LuCaP23, maintained in nude mice were similar to those of human prostate tissue and primary cultures. Both the xenograft and primary cultures from patients with prostate cancer may be more appropriate models than established cell lines for investigating techniques to increase the effectiveness of alkylators in prostate cancer.

Adenocarcinoma↗

PubMed1996

A phase II trial of amonafide, caracemide, and homoharringtonine in the treatment of patients with advanced renal cell cancer.

Forty-eight previously untreated, ambulatory patients with advanced or unresectable renal carcinoma were treated with either amonafide (17 patients), caracemide (17 patients), or homoharringtonine (14 patients). No objective responses were observed in any of the treatment cohorts. Amonafide and caracemide were well tolerated with no unexpected toxicities. One patient each died of pulmonary thromboembolism and sepsis with severe metabolic acidosis on the homoharringtonine arm. An additional 4 patients experienced grade 4 complications including myelosuppression, neurologic dysfunction, and respiratory failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced renal cell carcinoma.

Adenine↗

PubMed1996

Toxicity evaluation of difluoromethylornithine: doses for chemoprevention trials.

This intergroup trial was developed to determine the toxicity of relatively low doses of difluoromethylornithine (DFMO) administered to humans for 1 year. The goal was to find an appropriate DFMO dose for use in human chemoprevention trials. Patients with resected superficial bladder cancers were studied. Following stratification, they were randomized to daily DFMO doses of 0.125, 0.25, 0.5, or 1.0 g/day for a planned period of 1 year. Patients were followed closely for evidence of drug toxicity. Seventy-six patients were evenly randomized (19 per group) to receive each dose of DFMO. Forty-nine patients received DFMO for more than 200 days while 35 received the drug for > or = 350 days. No substantial drug-related toxicity was observed at any dose. DFMO doses of > or = 1 g/day for periods up to 1 year appear to be without significant toxicity in most patients. This dose range may be appropriate for use in future human cancer chemoprevention trials.

Antineoplastic Agents↗

PubMed1996

Carmustine and streptozocin in refractory melanoma: an attempt at modulation of O-alkylguanine-DNA-alkyltransferase.

The activity of the enzyme O6-alkylguanine-DNA-alkytransferase (AGAT) protects cells from the cytotoxic effects of alkylating agents. This Phase II trial was designed to assess the efficacy of a strategy designed to modulate the resistance to carmustine (BCNU) mediated by AGAT using streptozocin (STZ) in patients with advanced refractory melanoma. Seventeen patients who had failed prior chemotherapy were treated with STZ at 500 mg/m2 daily for 4 days with BCNU at 150 mg/m2 on day 3. Peripheral blood lymphocytes for assay of AGAT activity levels were collected prior to therapy and following the third dose of STZ. There were two partial responses in the 15 patients evaluable for response (13%). Most patients received only a single cycle of therapy due to rapidly progressive disease. Two patients developed fatal pulmonary toxicity, and one developed myelodysplasia. Other toxicities included transient rises in liver function tests. AGAT levels decreased by a mean of 53% in 9 patients but actually increased over baseline in 3 patients while on therapy. Based on these data, BCNU and STZ are not an effective combination for the therapy of advanced refractory melanoma, and pulmonary toxicity due to this combination appears to be increased compared with BCNU alone. STZ is not an effective modulator of AGAT activity when given on this schedule. New strategies designed to deplete AGAT activity using O6-benzylguanine or temozolomide should be explored with careful attention to the possibility that this approach may potentiate both the toxicity and efficacy of BCNU.

Adult↗

PubMed1995

A phase I trial of high-dose oral tamoxifen and CHOPE.

Drug resistance is a common phenomenon in clinical oncology. In vitro, tamoxifen has been shown to be an effective inhibitor of P-glycoprotein and a modulator of the multidrug resistance phenotype. We have previously shown that vinblastine can be given safely in combination with tamoxifen at doses that may modulate P-glycoprotein activity. In this phase I trial, tamoxifen (150 mg/m2 twice a day) was given with CHOPE (cyclophosphamide/doxorubicin/vincristine/prednisone/etoposide) in order to assess the toxicities of the combination. Resistance to three of these cytotoxic agents (doxorubicin, vincristine, and etoposide) may be mediated by P-glycoprotein. A total of 13 patients were evaluable on this trial, which showed that the maximum tolerated doses of cyclophosphamide and etoposide were 750 and 80 mg/m2, respectively. The dose-limiting toxicity was myelosuppression with 50% of the patients (3/6) treated at this dose level developing febrile neutropenia and 85% (6/7) developing grade 4 neutropenia. Tamoxifen at a dose of 150 mg/m2 twice a day can be given safely with the lymphoma regimen CHOPE at standard doses, but this combination may result in increased myelosuppression.

Administration, Oral↗

PubMed1995

A phase II study of interleukin-2 with and without beta-interferon in the treatment of advanced renal cell carcinoma.

BACKGROUND: Biologic response modifiers have activity in renal cell carcinoma. The combination of interleukin-2 (IL-2) and beta-interferon (B-IFN) is synergistic in vitro. This trial was initiated to determine the efficacy of IL-2 alone and with B-IFN in advanced RCC. METHODS: Ambulatory patients with advanced RCC were randomly allocated to either IL-2 6 x 10(6) units/M2 intravenously (IV) three days a week for four weeks or IL-2 5 x 10(6) units/M2 IV plus B-IFN 6 x 10(6) units/M2 IV three days a week for 4 weeks. This induction phase was followed by a maintenance phase of the same drugs and doses administered for two weeks out of every four. RESULTS: 84 patients were entered onto this phase II trial with 75 considered eligible for response and survival. Toxicity is reported for the 81 patients on whom data was received, irrespective of eligibility. The overall response rate (RR) was 9.3% (7/75). Of the 3 responses in the IL-2 arm (RR = 8.3%), one was a complete response. 4 patients in the IL-2 + B-IFN arm (RR = 10.3%) achieved a partial response. Median survival was estimated to be 8.4 months for patients given IL-2 and 8.0 months for patients given the IL-2 and B-IFN combination. Multivariate analysis of survival data identified initial performance status, metastases of > 1 site, and weight loss as being important prognostic factors for survival. There were 2 lethal and 3 life threatening toxicities with the IL-2 treatment. While there were no lethal toxicities on the combination arm, there were 4 life threatening toxicities. CONCLUSIONS: The results of this study indicate that further investigation of IL-2 with or without B-IFN at this dose and schedule as treatments for renal cell carcinoma is probably not warranted.

Adult↗

PubMed1995

Spinal cord compression in prostate cancer.

Approximately 200,000 men will be diagnosed with prostate cancer in 1994. While localized disease is potentially curable with surgery or radiation therapy, metastatic disease is incurable. The most frequent site of metastasis is bone. Spinal cord compression occurs in approximately 7% of men with prostate cancer. Back pain often heralds the diagnosis of spinal cord compression. In prostate cancer patients with back pain or signs of myelopathy or radiculopathy, plain radiographs of the spine and magnetic resonance imaging should be performed. Early diagnosis is of utmost importance. The neurologic status prior to treatment is the major determinant influencing outcome. Following diagnosis, corticosteroid therapy should begin immediately. Hormonal therapy should be instituted in those patients who have not previously undergone hormonal manipulation. The standard approach to definitive therapy is radiation. Surgical decompression plays a role in patients with severe myelopathy, spinal instability, and in those patients whose neurologic status deteriorates during or after radiation therapy.

Combined Modality Therapy↗

PubMed1995

Phase I/II dose-escalation study of liarozole in patients with stage D, hormone-refractory carcinoma of the prostate.

BACKGROUND: Liarozole binds to the cytochrome P-450-dependent hydroxylating enzymes involved in steroid biosynthesis and retinoic acid catabolism. This phase I study investigated the clinical/endocrine toxicity profile of liarozole and determined the maximally tolerated dose (MTD) in hormone-refractory prostate cancer patients. METHODS: Groups of five patients were treated with oral liarozole caplets, starting at 37.5 mg twice daily. The dose was doubled for each subsequent group until the MTD was reached, after which, an additional 18 patients were entered into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinically significant laboratory results. RESULTS: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effects that defined the MTD included lethargy, somnolence, body rash, and paresthesias. Two deaths occurred during the trial (pneumonia and myocardial infarction). Four patients had a > 50% decrease in prostate-specific antigen (PSA) levels (two at 150 mg, two at 300 mg). Of nine patients with measurable disease, two had partial responses. CONCLUSIONS: Liarozole was generally well tolerated with no evidence of adrenal insufficiency. Preliminary evidence of activity in this indication was observed based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.

Aged↗

PubMed1995

Population pharmacokinetics of hydroxyurea in cancer patients.

The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (Vmax), 0.097 mmol h-1 l-1; Michaelis constant for HU elimination (KM), 0.323 mmol/l; renal clearance (ClR), 90.8 ml/min; volume of distribution (Vd), 0.186 x (body weight) + 25.4 l; absorption rate constant (Ka), 2.92 h-1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration.

Administration, Oral↗

PubMed1995

Renal cell carcinoma: considerations for nephron-sparing surgery.

OBJECTIVES: The performance of nephron-sparing surgery in patients with a normally functioning contralateral kidney is controversial. To explore the risk factors that may contribute to the success or failure of nephron-sparing surgery, we examined the radiology and pathology reports of 278 patients who underwent radical nephrectomy for the treatment of clinically localized renal cell carcinoma. METHODS: We collated patient data from the records of 278 patients with Stage III renal cell carcinoma entered into the Eastern Cooperative Oncology Group protocol EST 2886 and compared preoperative clinical staging with postoperative pathologic results. Patients were considered potential candidates for nephron-sparing surgery if their preoperative radiographic studies indicated that the carcinoma was a single polar lesion 5 cm or less in diameter. RESULTS: Of 278 radical nephrectomy specimens, 36 had primary lesions 5 cm or less in diameter. Preoperative radiographic studies showed 14 of 36 would not have been considered eligible for nephron-sparing surgery. Of the remaining 22 potential candidates, pathologic studies showed multifocal lesions in 11, renal vein disease in 4, and nodal disease in 2. Only 5 of 22 patients might have had specimen-confined disease (T3a lesion). CONCLUSIONS: Capsular-penetrating (T3a) renal cell carcinoma is not often appreciated preoperatively and is associated frequently with multifocal lesions, renal vein or nodal disease. Frozen section studies to rule out T3a disease at the time of nephron-sparing surgery may help determine which patients need radical surgery.

Carcinoma, Renal Cell↗

PubMed1994

Clinical pharmacokinetics of cyclophosphamide and metabolites with and without SR-2508.

The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.

Cyclophosphamide↗

PubMed1994

An Eastern Cooperative Oncology Group phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma.

BACKGROUND: Trimetrexate is an antifol that differs from methotrexate in ways that may be clinically important. Because methotrexate has activity in advanced bladder cancer, this trial was initiated. METHODS: Ambulatory patients with advanced urothelial carcinoma were treated with the nonclassic antifol trimetrexate at the intravenous dose of 8 mg/m2 daily for 5 consecutive days every 3 weeks (4 mg/m2 daily for 5 consecutive days for patients with creatinine levels greater than 1.6 mg/dl). RESULTS: Of the 48 patients in the study, one had a complete response and seven had partial responses, for an overall response rate of 17% (exact 95% confidence interval, 7-30%). The response rate in patients who had received prior methotrexate was 18%, suggesting lack of complete cross-resistance. Toxicity was manageable and primarily mucosal, gastrointestinal, and myelosuppressive. CONCLUSIONS: Trimetrexate has as much activity as other single agents in advanced urothelial carcinoma. Combination therapy, possibly with cisplatin, platinum analogs, or other antifols, using trimetrexate should be studied.

Adult↗