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Y M Rustum

Publications and source records attributed to Y M Rustum.

At least 127 records · Page 7Linked to original sources
PubMed1989

Mechanisms of the in vivo resistance to adriamycin and modulation by calcium channel blockers in mice.

A sensitive fluorometric assay using Hoechst 33258 and a modified alkaline elution procedure were used to quantitate DNA single-strand breaks following an in vivo drug treatment of mice bearing P-388/S and P-388/R cells. After an i.p. treatment of mice with 1 to 20 mg/kg Adriamycin (DOX), the following differences between sensitive and resistant P-388 cells were observed: (a) at 2 h following drug treatment the net intracellular accumulation of Adriamycin in sensitive cells was 2- to 3-fold higher than resistant cells at all doses tested; (b) utilizing a therapeutic dose of DOX (10 mg/kg), the amount of single-strand breaks of DNA in sensitive and resistant cells was significantly different, K x 10(2) = 13.6 +/- 1.1 (SD) versus 3.6 +/- 0.9, respectively; (c) the 10 and 50% lethal doses for verapamil (VEP) were 10 and 23 mg/kg and for a tiapamil analogue, N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylam ine hydrochloride (DMDP), were 107 and 126 mg/kg, respectively; (d) while the in vivo intracellular accumulation and retention of DOX in sensitive cells were not affected by DMDP or VEP treatment, complete restoration of DOX accumulation and retention was achieved in resistant cells treated with well-tolerated doses of DMDP of 30 and 60 mg/kg. In contrast, utilizing the optimally tolerated dose of VEP (5 mg/kg), only partial restoration of DOX accumulation and retention in resistant cells was achieved; (e) DMDP or VEP did not alter the high level of DNA single-strand breaks induced by DOX in sensitive cells; in resistant cells, however, an increase in single-strand breaks of DNA was observed following treatment with DOX in combination with DMDP and to a lesser extent with VEP; and (f) the rapid DNA repair in resistant cells was inhibited by DMDP but not by VEP. These data demonstrate that DMDP but not VEP can effectively restore the in vivo intracellular accumulation of DOX in resistant cells at achievable nontoxic plasma concentrations. Previous studies have demonstrated that the in vitro intracellular concentrations and retention of DOX by resistant cells can be restored by VEP. The results reported herein demonstrated that similar effects can be achieved, however, in vivo by using a new calcium channel blocker, DMDP, with less in vivo toxicity and more efficacy than VEP in restoring cellular drug concentration, retention, and repair of DNA damage in the resistant cells.

Animals↗
PubMed1989

Toxicity and antitumor activity of 5-fluorouracil in combination with leucovorin. Role of dose schedule and route of administration of leucovorin.

Clinically, 5-formyltetrahydrofolate (leucovorin, folinic acid, LV) in combination with 5-fluorouracil (5-FU) has been used at various doses, schedules, and routes of administration with therapeutic benefit to patients with advanced colorectal carcinoma and breast carcinoma. Clinical experiences have been primarily with LV doses of 25, 200, and 500 mg/m2 administered by either short-term intravenous infusion, daily continuous infusion, or orally. In patients with lung carcinoma, oral administration of dl-LV at 125 mg/m2 hourly for 4 hours (total dose of 500 mg/m2) gave the following peak plasma folate concentrations: dl-LV, 4.6 + 1.9 microM; 5-methyltetrahydrofolate, 4.3 + 2.1 microM; and no detectable l-LV in most cases. The d-LV/5-methyltetrahydrofolate ratios, however, were lower for the oral route than for the same dl-LV dose administered by 2-hour intravenous infusion in the same patient. To determine if there is a relationship between the dose, schedule, or route of administration and the therapeutic efficacy of LV combined with 5-FU, studies were carried out in rats with transplantable colon carcinoma. 5-Formyltetrahydrofolate was administered at various doses by either 2-hour infusion, 2-day continuous intravenous infusion, or by divided hourly oral doses for 4 hours. In all cases, the total doses of dl-LV administered were 100, 200, and 400 mg/kg. Data obtained to date indicate: (1) plasma folate concentrations by intravenous administration were dose dependent, but lower and saturable concentrations of folates were observed by oral administration; and (2) while the concentrations of 5-methyltetrahydrofolate achieved by the 2-hour infusion schedule were relatively constant and independent of the dose of dl-LV administered, conversion of dl-LV to 5-methyltetrahydrofolate with the 2-day infusion of 100, 200, and 400 mg/kg was dose dependent. In humans, however, conversion was independent of the route of administration of dl-LV (19% for the 2-hour infusion and 23% for the 5-day infusion of 500 mg/m2 dose). Preliminary results for antitumor activity of 5-FU in combination with dl-LV, administered by either 2-hour intravenous infusion (400 mg/kg/day for 5 days) or orally (100 mg/kg/hour for 4 hours), yielded similar inhibition of in vivo tumor growth, each being greater than what was achieved with 5-FU alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Relationship between cytotoxicity, drug accumulation, DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933.

The effect of N-(3,4-dimethoxyphenyl) N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 microM as compared with 10 microM verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.

Calcium Channel Blockers↗
PubMed1989

Inhibition of implantation of murine bladder tumor by thiotepa in cauterized bladder.

This study was designed to determine the role of immediate intravesical instillation of single dose thiotepa post transurethral resection of bladder tumor in the prevention of recurrence by tumor implantation, using murine bladder tumor line 2 and 201 C3H/He mice. Previous studies have suggested implantation may take place as early as the first hour and reach its maximum in 24 hours after resection of bladder tumor. An in vitro dose response curve of MBT2 to thiotepa was established by treatment with various concentrations of thiotepa of 0.00, 0.01, 0.21, 0.44, and 1.91 mg./ml. In a group of 201 mice, the bladder was catheterized with a 24G angiocatheter, and a fine copper wire was inserted through the lumen. The bladder was cauterized by touching the wire with a Bovie coagulator for four seconds at the lowest setting. All bladders were instilled with 1 x 10(6) cells of murine bladder tumor line 2, followed by instillation of 1.91 mg./ml. of thiotepa with various time delays per treatment group. The bladder implantation rates were 30.4% (17/56), 3.4% (2/59), 6.5% (2/31) and 26.9% (7/26) in the control, immediate, one-hour delay and 24-hour delay groups, respectively. The urethral implantation rates were 21.4% (12/56), 0% (0/59), 6.5% (2/31) and 0% (2/26), respectively. The overall implantation rates (bladder, urethra, or both) were 42.9% (24/56), 3.4% (2/59), 6.5% (2/31) and 25.9% (7/27), respectively. Implantation rates were significantly higher in the control and 24-hour delay groups than in the immediate and one-hour instillation groups (p less than 0.05, Fisher Exact Test). We conclude from this animal model that intravesical instillation of single dose thiotepa, to be effective, should be initiated within the first hour after tumor resection, since it dramatically decreased the incidence of bladder and urethral implantation.

Administration, Intravesical↗
PubMed1989

The role of drug sequence in therapeutic selectivity of the combination of 5-fluorouracil and cis-platin.

The therapeutic efficacy of 5-fluorouracil (FUra) and cis-dichlorodiamine-platinum (cis-DDP) in mice bearing transplantable leukemia and solid tumors was evaluated using different sequences of combination of these agents. The optimal sequence was cis-DDP administered 24 h after FUra. The administration of FUra at its maximally tolerated dose (MTD) followed 24 h later by low doses of cis-DDP yielded less toxicity and higher response rate against L1210 and colon 26 than the administration of these two agents in the opposite sequence or concurrently at the MTD. The sequence of administration of these two agents was not therapeutically important when the antitumor activity was evaluated against mice bearing lymphoma P388. These results indicate that the importance of sequencing of FUra and cis-DDP varies among different tumors. The biochemical basis for the therapeutic importance of sequencing in treatments with cis-DDP and FUra was investigated in mice bearing leukemia L1210 cells. While cis-DDP has no significant effects on the activity of thymidylate synthase (dTMP-S), the target enzyme for FUra action, recovery of dTMP-S inhibition following pretreatment with FUra was significantly delayed when cis-DDP was administered 12-24 h after the initial dose of FUra.

Animals↗
PubMed1988

The effects of verapamil and a tiapamil analogue, DMDP, on adriamycin-induced cytotoxicity in P388 adriamycin-resistant and -sensitive leukemia in vitro and in vivo.

DMDP [N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl-m-dithane- 2-propylamine] a recently developed calcium antagonist analogue, caused a greatly increased intracellular retention of adriamycin and concomitant enhanced cytotoxicity in adriamycin-resistant P388 leukemia cells in vitro. These effects of DMDP were greater than those of another calcium channel blocker, verapamil, and occurred at one-half the dosage levels. Only slight enhancement in adriamycin toxicity was observed for either of these agents in the adriamycin-sensitive parental cell line. However, no significant therapeutic potentiation of adriamycin activity occurred with either verapamil or DMDP treatment in vivo. In vivo maximum DMDP tumor intracellular concentrations, as analyzed by HPLC, were the same in vitro tumor cell levels required to overcome adriamycin resistance. This inability to overcome drug resistance in vivo at acceptable levels of host toxicity is not only a function of maintaining necessary calcium antagonist concentrations in resistant tumor cells.

Animals↗
PubMed1988

Treatment of advanced-stage colorectal adenocarcinoma with fluorouracil and high-dose leucovorin calcium: a pilot study.

Thirty-one evaluable patients with measurable advanced colorectal carcinoma were entered into a pilot study that used weekly fluorouracil (5-FU) at the dose of 600 mg/m2 by bolus infusion administered midway during a two-hour leucovorin calcium infusion of 500 mg/m2. This regimen was repeated weekly for six doses. Twenty-seven of these patients (87%) were considered to be refractory to prior 5-FU therapy and four (13%) were previously untreated. All 31 patients successfully completed at least one 6-week cycle of this regimen with acceptable toxicity. The combined complete (CR) and partial response (PR) rate was 45% with another 25% of patients remaining stable. The 95% confidence levels for the responding patients are 27.6% and 62.7%, respectively. The remaining 30% of the patients had all received prior 5-FU therapy and progressed. All of the responding patients and 80% of the patients with stable disease received two or more cycles of this regimen after a 3- to 4-week interval off therapy. The median time to disease progression was 16.1 months for responding patients and 6.7 months for those patients with stable disease. The median survival for the responders was 20.6 months and for those with stable disease 9.8 months. The median survival for the nonresponding patients was 3.9 months. Toxicity included diarrhea in 70% of patients, skin rash (erythema) in 10%, stomatitis in 15%, nausea and vomiting in 25%, and myelosuppression in 10%. This study confirms and extends previous observations that demonstrate the improved efficacy of 5-FU when used with high-dose leucovorin in advanced colorectal carcinoma.

Adenocarcinoma↗
PubMed1988

Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma.

Plasma pharmacokinetics of high-dose (500 mg/m2) leucovorin calcium (dl-5-formyltetrahydrofolic acid [dl-CF]) and fluorouracil (FUra) have been evaluated in patients with advanced colorectal cancer treated with the combination of FUra and dl-CF by two different intravenous (IV) schedules: (A) In patients with no prior chemotherapy, dl-CF was administered by a two-hour IV infusion and FUra by rapid IV injection one hour after the start of the dl-CF infusion and (B) in previously treated patients, dl-CF and FUra were administered by five-day continuous IV infusion (CI). Following the two-hour infusion of dl-CF, mean peak plasma concentration and elimination half-life of I-5-formyltetrahydrofolic acid (I-CF) were 24 +/- 6 mumol/L and 0.8 +/- 0.1 hour, respectively. CI of dl-CF over five days yielded a mean steady-state plasma level of I-CF of only 1.2 +/- 0.5 mumol/L. Peak and steady-state plasma concentrations of the metabolite 5-methyl tetrahydrofolic acid were comparable in the two schedules (17 +/- 8 mumol/L for the two-hour infusion and 12 +/- 5 mumol/L for the CI). Areas under the concentration v time curve (AUC) of total reduced folates were significantly greater under conditions of CI: 89.0 v 16.7 mmol/L/min for the two-hour infusion. In tumor tissue, 5,10-methylenetetrahydrofolate increased eight-fold two to four hours following the two-hour infusion and two-fold during the CI of dl-CF and FUra. Inhibition of thymidylate synthase (dTMP-S) by the two-hour and CI infusion schedules were 66% v 39%, respectively. The observed differences in the intracellular dTMP-S folate cofactor pools and the degree of inhibition of dTMP-S achieved in patients treated by two different schedules may be due to differences in the biochemical properties and/or to differences in the modulation of FUra metabolism by folate of tumor tissues obtained from newly diagnosed and previously treated patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Abrogation of the prognostic significance of low leukemic cell retention of cytosine arabinoside triphosphate by intensification of therapy and by alteration in the dose and schedule of administration of cytosine arabinoside.

The ability of leukemic cells to phosphorylate cytosine arabinoside (araC) and retain the triphosphate form of the drug (araCTP) is strongly predictive of remission duration for patients with acute nonlymphocytic leukemia who are treated with araC-based maintenance therapy. An increase in the intensity of therapy improves the overall median duration of remission, the increased intensity of therapy being especially beneficial for patients whose leukemic cells do not retain araCTP. This alteration in therapy reduces the prognostic significance of leukemic cell araCTP retention. Further, it seems that the use of high-dose araC as intensive consolidation therapy and the administration of conventional-dose araC by continuous infusion make it possible to further reduce or even abrogate the adverse prognostic significance of low leukemic cell retention of araCTP.

Acute Disease↗
PubMed1987

Biological activities of 5-fluorouracil and its prodrug 5'-deoxy-5-fluorouridine in rats.

The antitumor activity and toxicity of 5-fluorouracil (FUra) and 5'-deoxy-5-fluorouridine (dFUR) were compared in female Fischer rats bearing transplanted dimethylhydrazine-induced colon tumors. The therapeutic effects of FUra and dFUR were not affected by the initial tumor size, but were dependent on the dose and duration of treatment. The maximal response rate of 80-90% cures was obtained with 7-day infusions of 35 mg-kg-1-day-1 FUra or 500 mg-kg-1-day-1 dFUR. The host toxicity of FUra and dFUR in tumor-bearing or normal rats included gastrointestinal and central nervous system disturbances. Toxicity related death was preceded by a greater than 20% animal weight loss and other signs of gastrointestinal disturbances. The maximal therapeutic dose of FUra was identical to the toxic dose which caused 40% death in normal rats. By contrast, the maximal therapeutic dose of dFUR did not cause toxic death, and the threshold lethal dose of dFUR was 40% higher than the maximally therapeutic dose, indicating a better therapeutic index for dFUR in this rat tumor.

Animals↗
PubMed1987

A phase II trial of 5-fluorouracil and high-dose intravenous leucovorin in gastric carcinoma.

Twenty-eight patients with advanced measurable gastric carcinoma were treated with leucovorin (dl-CF; folinic acid; dl-5-formyltetrahydrofolic acid) 500 mg/m2 administered as a two-hour infusion and 5-fluorouracil (5-FU) 600 mg/m2 intravenous (IV) push midinfusion. Treatment was administered weekly for 6 weeks followed by a 2-week rest. Twenty-five patients were evaluable for response. Twelve of them had received previous combination chemotherapy that included 5-FU. Median age was 59 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. Three patients had partial responses and two of them had been treated previously with 5-FU. Twelve patients had stable disease. Five of these patients had subjective improvement with improved performance status and/or decreased dysphagia. The 95% confidence interval for response is 3% to 32%. Median survival time for all 28 patients enrolled in the study was 22 weeks. Toxicity was moderate and consisted primarily of diarrhea. Myelosuppression, skin rash, and increased lacrimation also occurred. Plasma concentrations of the active reduced folates, I-CF and 5-methyltetrahydrofolic acid (5-CH3FH4), were greater than the 10 mumol/L levels that potentiate 5-FU activity in in vitro models, for more than four hours in all five patients in whom pharmacokinetics were studied. 5-FU and high-dose dl-CF has activity in patients with gastric carcinoma including patients who had previously progressed on 5-FU-containing combinations. Further study in a larger patient population is necessary to determine the usefulness of this regimen in gastric carcinoma.

Adenocarcinoma↗
PubMed1987

P-glycoprotein in human sarcoma: evidence for multidrug resistance.

Overexpression of an immunologically conserved, cell-surface glycoprotein (P-glycoprotein) is consistently associated with multidrug resistance in cell lines in vitro. A preliminary survey of specimens from 12 solid tumor types in our laboratories indicates significant overexpression of P-glycoprotein in some sarcomas. When tested by immunoblotting with monoclonal antibodies directed against P-glycoprotein; tumors from six of 25 sarcoma patients displayed elevated levels of P-glycoprotein. Three of the sarcoma patients exhibiting P-glycoprotein had not previously been exposed to chemotherapy, implying that overexpression of this marker and possible concomitant multidrug resistance may not depend only on selection during prior drug treatments. The P-glycoprotein overexpression in the sarcoma specimens is evidence for the presence of multidrug resistant cells in these tumors; thus, our data suggest that this mode of resistance may have clinical significance in sarcoma patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1987

Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin.

In vitro and in vivo studies have been carried out in mouse and human tumors to investigate the biochemical and pharmacologic basis for the selectivity of 5-fluorouracil (FUra) action. Combination chemotherapy with FUra and thymidine was performed to determine the therapeutic relevance of 5-fluorouridine triphosphate (FUTP) incorporation into RNA. The results of these studies indicate that modulation of FUra cytotoxicity by deoxythymidine (dThd) did occur but failed to produce any significant therapeutic advantages in patients with advanced colorectal cancer. Modulation of FUra bioactivation via the deoxyribonucleotide pathway by coadministration of high-dose folinic acid resulted in enhanced therapeutic response rate of gastrointestinal tumor patients. This manuscript summarizes the preclinical and clinical findings on the metabolic modulation of FUra activity by dThd and folinic acid.

Animals↗