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Biomedical subjects

Y M Rustum

Publications and source records attributed to Y M Rustum.

At least 145 records · Page 8Linked to original sources
PubMed1987

Role of administration route in the therapeutic efficacy of doxifluridine.

Effect of drug administration route on the therapeutic efficacy of the 5-fluorouracil (FUra) analogue doxifluridine [(5'-dFUrd); 5'-deoxy-5-fluorouridine] was investigated in Fischer CDF rats bearing a chemically induced transplantable colon carcinoma sensitive to fluoropyrimidines. The antitumor activities of 5'-dFUrd and of its parent drug FUra were evaluated after 7 days of continuous administration (by iv infusion, iv push, or po route) of doses ranging from 125 to 750 mg 5'-dFUrd/kg/day and from 12.5 to 55 mg FUra/kg/day. At the maximally tolerated dose, 5'-dFUrd (500 mg/kg/day) and FUra (25-35 mg/kd/day) were equally effective in producing cures when treatments were performed by either continuous iv infusion or iv push. 5'-dFUrd was more effective than FUra when these agents were administered orally (82% cures for 5'-dFUrd vs. 30% cures for FUra). Concentrations of 5'-dFUrd and its metabolite FUra in the blood and urine of normal and tumor-bearing rats were determined by high-performance liquid chromatography following administration of 500 mg 5'-dFUrd/kg. Pharmacokinetic studies indicated that at comparable antitumor activity, systemic exposures to FUra derived from 500 mg 5'-dFUrd/kg administered by iv push, orally, or continuous iv infusion were 3.5 +/- 1.0, 3.2 +/- 1.1, and 1.5 +/- 0.3 mM X min, respectively. Antitumor activity and pharmacokinetic results obtained in this model system indicated that 5'-dFUrd is an active agent that can produce cures regardless of the route of administration employed and among the three methods of drug administration tested, comparable tumor-free survival can be achieved by continuous iv infusion of 5'-dFUrd with the concomitant lowest systemic exposure to the cytotoxic metabolite FUra.

Administration, Oral↗
PubMed1987

Effects of liposome-entrapped doxorubicin on liver metastases of mouse colon carcinomas 26 and 38.

The effects of doxorubicin (DOX) and DOX entrapped in standardized liposomes [mean diameter, 0.15 micron; (DOX-Lip)] on the survival of mice bearing liver metastases of mouse colon carcinoma CT38LD (C57BL/6J mice) or CT26 (BALB/c mice) were investigated. In vitro cultured CT38LD cells were more sensitive to DOX than CT26. In vivo DOX and DOX-Lip, administered iv 10 mg/kg weekly to a maximum of five injections, increased the life-spans of mice bearing CT38LD liver metastases 32% (P less than .05) and 64% (P less than .05), respectively. DOX-Lip was more effective than DOX in prolonging survival (P less than .05). Free DOX did not significantly increase the life-spans of mice bearing CT26 liver metastases (P greater than .5), whereas DOX-Lip increased the life-spans 35% (P less than .05). The results suggest that liposomal delivery of agents to the liver can enhance therapeutic activity and could be used as an arm of protocols for adjuvant therapy of liver metastases.

Animals↗
PubMed1987

Biologic modulation of 5-fluorouracil with high-dose leucovorin and combination chemotherapy of 5-fluorouracil and cisplatin in metastatic colorectal adenocarcinoma.

The data from an ongoing 3-arm prospective study of 72 patients with advanced colorectal carcinoma is presented. The 3 regimens are as follows: Regime 1 (every 4 weeks)--5-fluorouracil (FUra) (450 mg/m2 iv bolus daily for 5 days, then 200 mg/m2 iv bolus every other day for 6 doses); regime 2 (every week for 4 weeks, then every other week)--methotrexate (MTX) (50 mg/m2 in a 4-hour infusion) followed by FUra (600 mg/m2 iv bolus); regime 3 (weekly for 6 weeks followed by a 2-week rest period)--D,L-leucovorin (D,L-CF) (500 mg/m2 in a 2-hour infusion) with FUra (600 mg/m2 iv bolus) 1 hour after the D,L-CF infusion began. All monitoring lesions except lung were documented by tissue biopsy. Thirteen of 18 patients in the FUra + D,L-CF arm were evaluable for response. Six of the 13 patients (46%) have had a partial response. The duration of the 6 responses has been 11, 8, 7, 4, 3 and 3 months. In patients with liver metastases as the monitoring lesion, a dramatic improvement in liver function tests has been seen during the first 2 courses (12 weeks) of treatment, but this was not sustained. The toxicity of FUra + D,L-CF was predominantly gastrointestinal; unlike with FUra alone, myelosuppression was not predominant.

Adenocarcinoma↗
PubMed1987

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

Twenty-five patients with advanced measurable gastric carcinoma were treated with D,L-leucovorin (CF) (500 mg/m2) administered as a 2-hour infusion and FUra (600 mg/m2) iv push midinfusion. Patients were treated weekly for 6 weeks followed by a 2-week rest. Median age was 57 (range 32 to 82). Median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0 to 4). Thirteen patients had progressed on previous combination chemotherapy that included FUra. At the time of this report, 19 patients were evaluable for response: 3 patients had partial responses, 8 had stable disease, and 8 progressed (but 3 of these received only 3 or fewer treatments before early disease-related death). Two of the responders were previously treated with FUra. Four patients were too early to evaluate. Measurable responses of greater than 50% were seen in bone, liver, lung, and an abdominal mass. Diarrhea occurred in 9 patients and FUra dose reduction was necessary in 8 of them. Other toxicities included lacrimation, rash, nausea, and mucositis. One toxic death occurred. Nine patients with gastrointestinal tumors confined primarily to the intra-abdominal space were treated with ip FUra in escalating doses (2 mM to 4 mM) in combination with D,L-CF in a 2-liter volume, either by 8 consecutive 4-hour dwells (7 patients) or once daily for 5 days (2 patients). The D,L-CF dose was 20.8 microM except for the first day of the 5-day schedule when it was 104 microM. Toxicity included leukopenia, mucositis, nausea and vomiting, skin rash, and abdominal pain. Three episodes of peritonitis resolved with antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Bioavailability of high-dose oral leucovorin.

Fifteen adult subjects comprised the study group; 2 were colon cancer patients. Total leucovorin (citrovorum factor; CF) doses of 200, 400, 800, and 1600 mg were equally subdivided and administered at 0, 1, 2, and 3 hours. Three of the subjects were fasting and the other 12 were not. Quantitation of serum L-CF by Pediococcus cerevisiae and total reduced folates (TRF) by radio-assay were performed in 10 samples from each subject drawn over a 12-hour period after initiation of CF dosing. The mean serum levels of L-CF remained greater than 0.1 microM at 3 hours and the TRF 3.5 microM at 5 hours, respectively, after termination of CF dosing in all subjects treated at the 800- and 1600-mg dose schedule. At all CF dosage schedules employed, peak serum concentrations were reached within 4 and 6 hours after initiation of oral CF. Peak TRF concentrations at the 200-, 400-, 800-, and 1600-mg doses were 3.42 +/- 0.65, 4.05 +/- 1.04, 4.81 +/- 0.14, and 5.11 +/- 1.81 microM, respectively. Peak L-CF levels at 200, 400, 800, and 1600 were 0.15 +/- 0.11, 0.21 +/- 0.14, 0.23 +/- 0.11, and 0.34 +/- 0.16 microM. Based upon these observations, the following conclusions were reached: 1) no significant differences were observed in serum concentrations of folates between the 800- and 1600-mg dose schedules; 2) at these doses serum concentrations of L-CF and TRF were achieved that warrant a phase I investigation of high-dose oral CF with standard dose FUra in patients with advanced colorectal carcinoma.

Administration, Oral↗
PubMed1986

Growth of human urologic tumors on extracellular matrix.

Surgical specimens of fifty urologic tumors, 19 renal, 19 bladder, nine prostate and three testicular, were disaggregated into a cell suspension by a two step mechanical and enzymatic method. Viability, cytology and flow cytometry (FCM) for DNA ploidy were subsequently determined. Growth of urological tumors on extracellular matrix (ECM) was carried out as follows: 2.5 to 5 X 10(5) cells were placed in plastic T25 flasks in RPMI 1640 + 10 per cent fetal bovine serum (FBS). 1.0 to 5 X 10(4) cells were plated in wells coated with ECM derived from bovine corneal endothelial cells with RPMI 1640 + 10 per cent FBS. Cultures were incubated for seven to 10 days at 37 degrees C. Only one (renal) out of 28 tumors grew on plastic. Forty out of 50 tumors (80 per cent) established primary cultures on ECM as determined by cell counting, protein determination, and/or [3H]thymidine incorporation. Previous experience with 106 urologic tumors grown on double layer agar demonstrated an overall success rate of 48 per cent. On ECM renal tumors showed 95 per cent growth success, prostate 89 per cent, bladder 63 per cent and testicular 67 per cent. Unlike viability by trypan blue exclusion, tumor DNA ploidy and percentage of malignant cells plated on ECM had no effect on growth success. The malignant nature of the cultured cells was confirmed by cytology. Twelve high grade and metastatic tumors caused degradation of the ECM. DNA ploidy was similar in four and different in six tumors before and after culture. Five tumors underwent in vitro drug testing on ECM with significant growth inhibition observed in three cases. The extracellular matrix seems to be a promising model for growing urologic tumors with excellent potential for drug testing in vitro.

Antineoplastic Agents↗
PubMed1986

Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer.

Many patients with gastrointestinal (GI) tumors develop extensive peritoneal and serosal metastasis and/or malignant ascites which respond poorly to available treatments. Twelve patients with tumors confined primarily to the intraabdominal cavity were treated with intraperitoneal (IP) 5-fluorouracil (5-FU) in escalating concentrations (2 to 4 mmol/L) in combination with leucovorin (dl-5-formyltetrahydrofolic acid or folinic acid; dl-CF) in a 2-L volume, either by eight consecutive four-hour dwells or once daily for five days. CF dose was 20.8 or 104 mumol/L. Nine of the patients had pancreatic carcinoma, one had stomach carcinoma, and two had hepatobiliary neoplasms. Median age was 62.5 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 3. Toxicity included mucositis, diarrhea, nausea and vomiting, leucopenia, skin rash, and abdominal pain, and was similar to that previously reported for IP 5-FU used as a single agent. Four episodes of peritonitis occurred, but all patients responded to antibiotics. At the 20.8 mumol/L dose, dl-CF concentration in the peritoneal fluid declined from 10.4 +/- 3.0 3.0 mumol/L at one hour to 4.9 +/- 2.2 mumol/L at four hours, corresponding to a mean absorption half-life of 127 +/- 49 minutes and a mean peritoneal clearance of 13.0 +/- 4.5 mL/min. Decline was biphasic in all but five of the 19 exchanges evaluated. The levels of l-CF (biologically active isomer of dl-CF) were 2.8 +/- 2.5 mumol/L after 60 minutes and 1.2 +/- 0.7 mumol/L after four hours. The peritoneal area under the concentration v time curve (AUC) for 5-FU increased proportionally with dose. For example, the AUC at 2.0 and 3.5 mmol/L was 129 +/- 25 and 201 +/- 23 mmol/L X minute, respectively. However, the maximal peritoneal to plasma AUC ratio was 461 at the 2 mmol/L dose, but decreased with increasing doses as systemic clearance decreased. This regimen was well tolerated in patients with advanced cancer, but must be evaluated further to determine its clinical efficacy.

Abdominal Neoplasms↗
PubMed1986

Approaches to overcome in vivo anti-cancer drug resistance.

Therapeutic efficacy of anticancer drugs against malignant diseases is limited because of the selection and regrowth of drug resistant cells. This problem is compounded by the development of cross-resistance to other useful chemotherapeutic agents which severely limits treatment alternatives. Development of approaches to overcome and/or circumvent drug resistance will depend on the precise understanding of the mechanism(s) of resistance not only at the target tumor cell level (in vitro) but also in vivo. The data on L1210 sensitive to araC transplanted s.c. demonstrated that although target cells are highly sensitive to araC, the lack of in vivo response of solid L1210 cells (s.c.) is primarily due to limited drug delivery to the target. Approaches that would modify these processes should improve on the therapeutic selectivity of this agent. In contrast, in cells where the mechanism of resistance is deletion of a key anabolic enzyme (e.g. CdR kinase), these cells are collaterally sensitive in vitro and in vivo to DAUR. This type of resistance, however, could not be overcome by liposome encapsulation of araC or araCTP. With respect to AM resistance, the concentration of VRP for in vitro reversal of resistance of P-388/AM was difficult to achieve in vivo without significant host toxicity. Continuous infusion of VRP, however, demonstrated that at the maximally tolerated doses of VRP it was not possible to achieve any significant therapeutic effects against P-388/AM. The use of liposomes or modulation by VRP does not appear to be a fruitful approach in overcoming AM resistance, especially in cells which possess a high degree of resistance. Metabolic modulation of FU by dLCF appears to be a promising area of investigation and deserves further investigation concerning quantitation of the intracellular pools of folate and ways to modulate them.

3-Deazauridine↗
PubMed1986

Growth of human urological tumors on extracellular matrix as a model for the in vitro cultivation of primary human tumor explants.

The goal of this study was to establish an optimal in vitro growth assay system for human urological tumor explants. Bovine corneal endotelial cell extracellular matrix (ECM) coated dishes were evaluated as a growth substrate for tumor cultures. Growth success for different urological carcinomas (prostatic, bladder, kidney, and testicular) was compared after seeding fresh surgical explants onto bovine corneal endothelial cell ECM and plastic culture flasks. Tumor samples were disaggregated enzymatically, and 1 X 10(4) cells were seeded onto the different substrates using RPMI 1640 medium containing 10% fetal calf serum and/or different growth factors, nutrients, and hormones. Cell growth on ECM was quantitated on days 7-15 by [3H]thymidine uptake, cell counting, and total protein. Tumor cells were characterized by flow cytometry and cytology. It was observed that ECM provides superior culture conditions for urological carcinomas. By increasing the initial number of cells plated on ECM and by adding different growth factors or hormones, the growth rate for specific tumor types was increased significantly. Several tumors (11 cases) grown on ECM were examined under the light microscope, and in all cases pre- and post-cytology confirmed malignancy. Tumor cells maintained on ECM and transplanted into nude mide retained their tumorigenic and morphological characteristics. Clinically aggressive tumors were associated with extensive ECM degradation. In addition, the growth of fresh human tumors on ECM provides a biologically relevant model system (for assessing the invasiveness of tumors in vitro) and should also be useful for drug evaluation studies.

Cell Adhesion↗
PubMed1985

Comparison of the membrane-related effects of cytarabine and other agents on model membranes.

UNLABELLED: The membrane-associated effects of a series of chemotherapeutic and other drugs were examined via differential scanning calorimetry and by their modulation of the action of porcine phospholipase A2 (PLA2) on bilayer substrates. The drugs examined included: cytarabine, amino-glycoside antibiotics, adriamycin, dibucaine, butacaine, and VP-16. The bilayers employed were phase-separated ternary lipid mixtures containing dimyristoylphosphatidylcholine: palmitoyllysolecithin: and either hexadecanoic acid (fatty acid ternary mixture) or hexadecanol (alcohol ternary mixture). Effects of the more hydrophilic drugs (cytarabine and aminoglycoside antibiotics) on the calorimetric profiles of the negatively charged (fatty acid-containing) and the neutral (hexadecanol-containing) ternary lipid mixtures indicate that the interaction of these drugs with biomembranes is likely to be dominated by electrostatic interactions. All of the drugs investigated, including the more hydrophobic adriamycin, dibucaine, butacaine, and VP-16, affected the phase equilibrium in the membrane and exhibited apparent noncompetitive inhibition of the action of PLA2 on bilayers composed of ternary lipid substrates. In addition, cytarabine inhibited fusion of fatty acid-containing ternary mixtures. CONCLUSIONS: These drug:membrane interactions leading to a shift in the phase equilibria were apparently regiospecific. Hydrophilic drug:membrane interactions included an important electrostatic component. The effects of all of the drugs employed in this study on the action of PLA2 on a bilayer substrate (fatty acid-containing ternary lipid mixture) are hypothesized to be a result of the drug-mediated shift in phase equilibria away from the optimally active phase distribution. As a result, PLA2 binds with normal affinity to the membrane, but its membrane substrate is not catalytically turned over. It is evident that these drugs can directly affect cellular homeostasis in a manner that can show a dependence on the nature of the membrane surface.

Anti-Bacterial Agents↗
PubMed1985

Flow cytometric analysis of DNA content in human bladder tumors and irrigation fluids.

Flow cytometry (FCM) was used to study the DNA distribution of 99 tumor biopsy specimens and 41 bladder irrigation samples from patients with transitional cell carcinoma of the bladder. For tumor biopsy and cystectomy specimens, the frequency of aneuploidy increased with advancing tumor stage and grade. All T0 tumors were diploid. Twenty-seven percent of T1, 71.4% of T2, and 75% of T3 and T4 tumors were aneuploid. All Grade I tumors were diploid. Thirty percent of Grade II and 76.9% of Grade III tumors were aneuploid. The frequency of aneuploidy of tumors in the early stages (Ta, T1) is similar to the incidence of subsequent progression by these tumors described in the literature. For irrigation fluids, the relationship between grade and stage and the frequency of aneuploidy was similar to the relationship seen with tumor specimens. All four patients with only carcinoma in situ had aneuploid cells in their irrigations. The comparison of FCM data of bladder biopsy and bladder irrigation from the same cystoscopic evaluation suggests adequate representation of tumor cells in the irrigation fluids for almost all cases. The authors conclude that DNA ploidy analysis by FCM appears useful in a clinically important group of patients with aneuploid superficial tumors of moderate or high grade. Bladder irrigation analysis appears useful in the follow-up of patients with a history of carcinoma in situ and those with aneuploid tumors.

Carcinoma, Transitional Cell↗
PubMed1985

1-beta-D-arabinofuranosylcytosine metabolism and incorporation into DNA as determinants of in vivo murine tumor cell response.

In this study, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) formation, retention, and incorporation into DNA were simultaneously evaluated in vivo in mice bearing leukemia cells sensitive to 1-beta-D-arabinofuranosylcytosine (ara-C) (L1210/0), leukemia cells resistant to ara-C (L1210/R), P288, and lymphosarcoma P1798, namely cells characterized by differential sensitivity to ara-C. In L1210/R cells, resistance to ara-C was correlated with low deoxycytidine-cytidine kinase activity (0.04 nmol/mg protein/min), with a low level of intracellular accumulation of ara-CTP, with a low level of incorporation of ara-C into DNA, and with no significant inhibition of thymidine incorporation into DNA. Thus a simple measurement of the intracellular pool of total ara-C nucleotides is sufficient to identify cells with this type of resistance. In contrast, in cells with sufficient deoxycytidine-cytidine kinase activity (greater than 0.1 nmol/mg protein/min), the factors determining the quality of response to ara-C could be distinguished as follows: (a) those which are responsible for in vitro cytotoxicity (producing in vivo cytoreduction); and (b) those which are responsible for in vivo selectivity (producing long term survivors). In P288 cells which are sensitive in vitro to ara-C, the determining factor for this sensitivity is the amount of ara-CTP formed which produced greater than 80% inhibition of thymidine incorporation into DNA. The lack of antitumor activity in vivo, however, was due to similarities in ara-CTP retention in target tumor cells (P288) and normal bone marrow cells. In both cases, ara-CTP retention at 4 h was less than 10% of the value obtained at 30 min. In contrast, in cells such as L1210 and P1798 long term survivors (cures) were directly correlated with higher ara-CTP retention. For example, 4 h after drug administration, ara-CTP retentions were 20, 82, and 6% for L1210, P1798, and bone marrow cells, respectively. At 24 h, 20% ara-CTP was retained intracellularly by P1798 tumor cells. In summary, results presented herein demonstrate the importance of differential ara-CTP retention as the most critical determinant of response for the induction of long term survivors, and ara-C incorporation into DNA by tumor cells after in vivo treatment appears to be less significant. These data also demonstrate close correlation between ara-CTP pools, retention, and the extent of inhibition of recovery of thymidine incorporation into DNA.

Animals↗
PubMed1985

Selective modulation of 5-fluorouracil action in patients with colorectal carcinoma.

Attempts to modulate by normal metabolites the intracellular metabolism of 5-fluorouracil (FU) via the ribonucleotide pathway leading to increased incorporation of the drug into RNA have been shown to potentiate host toxicity but not the therapeutic efficacy of this agent in preclinical model systems and in patients with advanced colorectal carcinomas. Recent advances aimed at the modulation of FU metabolism by CF via the deoxyribonucleotide pathway leading to prolonged inhibition of dTMPS activity indicates that the therapeutic efficacy of FU can be enhanced significantly in patients with advanced colorectal carcinoma. Pharmacokinetic studies of FU and CF revealed large intrasubject variations. In this presentation, rationale and the results of approaches taken at the preclinical and clinical levels in an attempt to selectively modulate the therapeutic efficacy of fluoropyrimidine will be discussed. This includes the importance of integration of information concerning pharmacokinetics and cellular metabolism in the design of optimal combination chemotherapy of FU with metabolic modulators.

Animals↗
PubMed1985

The use of liposomes as carriers of therapeutic agents.

Adriamycin (Doxorubicin) is an important chemotherapeutic agent, but is limited in its clinical usefulness by dose-related cardiomyopathy. Attempts are being made to reduce this toxicity while retaining anti-tumor activity. These include development of chemically modified anthracycline derivatives and coupling of adriamycin to or into macromolecular carriers. We and several other laboratories have shown that entrapment of adriamycin in liposomes (phospholipid vesicles) can reduce toxicity while retaining or, in some cases, enhancing anti-tumor activity. Here we report further results of experiments in mice on toxicity reduction and anti-tumor activity. Approximate maximum tolerated doses (MTD) of adriamycin were determined from normal mouse survival at 240 days after initial treatment. I.V. bolus injection of liposomal-adriamycin was superior to i.v. bolus or i.v. infusion of free drug after a single injection, 5 daily injections or 5 biweekly (every 2 weeks) injections. Using L1210 tumor as a model for systemic leukemia, liposomal adriamycin was as effective as free adriamycin at equal doses, however liposomal-adriamycin was more effective at MTD. M5076 tumor was used as a limited model for comparisons of the effects of liposomal-adriamycin on "primary" and "metastatic" disease. The results showed that whereas free and liposomal adriamycin were without significant effect on "primary", subcutaneous tumor, that liposomal adriamycin, but not free adriamycin had very strong effects on liver "metastases". The results suggest that liposomally administered drugs, including adriamycin, may have utility for treatment of certain types of cancer and for metastases in organs where liposomes accumulate. Where improved anti-tumor activity is coupled with toxicity reduction and simplicity of administration, liposomal administration could be a useful method of drug delivery.

Animals↗