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Biomedical subjects

J L Grem

Publications and source records attributed to J L Grem.

At least 91 records · Page 5Linked to original sources
PubMed1990

Enhancement of the toxicity and DNA incorporation of arabinosyl-5-azacytosine and 1-beta-D-arabinofuranosylcytosine by cyclopentenyl cytosine.

We evaluated the interaction of a biochemically active concentration of cyclopentenyl cytosine (CPE-C), an investigational antimetabolite which inhibits CTP synthetase, on the cytotoxicity of arabinosyl-5-azacytosine (Ara-AC) and 1-beta-D-arabinofuranosylcytosine (Ara-C) in HCT 116 colon carcinoma cells. A 3-h exposure to 0.5 microM CPE-C depleted CTP pools by over 90% and decreased dCTP pools by 57%; the effect on CTP pools persisted for up to 24 h following washout of CPE-C. A 3-h pre-exposure to 0.5 microM CPE-C augmented the growth inhibition resulting from a 24-h exposure to Ara-AC. The combination of 1 microM cytidine and deoxycytidine fully reversed the enhancement associated with CPE-C pretreatment, to a level of growth inhibition expected from either CPE-C or Ara-AC alone. A striking enhancement of toxicity was observed in clonogenic studies with pre-exposure to CPE-C at a nonlethal dose followed by either Ara-AC or Ara-C. CPE-C increased the formation of Ara-AC and Ara-C nucleotides by as much as 3-fold, and this was accompanied by increased incorporation of the arabinosyl nucleotides into methanol-precipitable material. Analysis of purified RNase-treated nucleic acids by cesium sulfate density centrifugation confirmed that a 3-h pre-exposure to CPE-C increased [3H]-Ara-C incorporation into DNA at 4 and 24 h by 2.4- and 2.7-fold, respectively. Thus, these studies indicate that CPE-C can function as a biochemical modulator. Following a brief exposure to a nonlethal concentration, CPE-C is capable of augmenting the cytotoxicity and intracellular metabolism of Ara-AC and Ara-C.

Antimetabolites, Antineoplastic↗
PubMed1990

Phase I trial of 5-fluorouracil and dipyridamole administered by seventy-two-hour concurrent continuous infusion.

Forty-seven patients with advanced malignancies were treated with a concurrent 72-h continuous infusion of 5-fluorouracil (FUra) and dipyridamole. The FUra dose was escalated over the dose range of 185 to 3600 mg/m2/day for 3 days. Dipyridamole was administered in a fixed dose of 7.7 mg/kg/day for 3 days. A total of 155 courses of therapy were completed of which there were 31 paired courses of the combination and FUra alone, at the same dose of FUra and in the same patient. This was for purposes of analysis of pharmacokinetics and modulation of FUra toxicity by dipyridamole. Stomatitis was the dose-limiting toxicity experienced by patients entered into this trial. Myelosuppression was not a serious problem. Increasing FUra plasma concentration was associated with greater leukopenia and stomatitis. Dipyridamole did not appear to modulate the systemic toxicity of FUra. The pharmacokinetics of FUra were altered by the concurrent administration of dipyridamole. Dipyridamole promoted the total body clearance of FUra which resulted in lower mean steady-state FUra plasma concentrations when compared with courses of FUra alone administered at the same dose level. These differences were statistically significant over the course of the trial. For courses of the combination, FUra exhibited linear pharmacokinetics over the dose range studied. Total body clearance of FUra declined slightly at the higher dose levels, but the differences were not significant. For courses of FUra alone, total body clearance was significantly decreased above the dose level of 2300 mg/m2/day. At the maximal tolerated dose of FUra, 2300 mg/m2/day x3, mean steady-state FUra plasma concentration and total body clearance were 6.6 microM and 122 liters/h/m2, respectively, for courses of the combination. The corresponding pharmacokinetic parameters were 7.4 microM and 103 liters/h/m2 for courses when FUra was given alone. Further evaluation of the utility of this regimen and basis of these pharmacokinetic observations appear warranted.

Adult↗
PubMed1990

Hypersensitivity reactions to trimetrexate.

Trimetrexate is a nonclassical antifol currently being tested for efficacy in cancer patients and as an antiparasitic agent against Pneumocystis carinii pneumonia in AIDS patients. We have now received the first reports of hypersensitivity reactions in Phase II cancer trials. Two types of reactions were noted. The most severe reaction, immediate hypotension with loss of consciousness, occurred in only one patient. Four other patients exhibited an immediate systemic effect with one or more of the following symptoms: facial flushing, fever, shaking, pruritus, bronchospasm, periorbital edema, and difficulty in swallowing. Immediate hypersensitivity should now be considered a known side effect of trimetrexate therapy, occurring in less than 2% of patients.

Adult↗
PubMed1990

Clinical toxicity associated with tiazofurin.

Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (greater than or equal to grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 microM) and prolonged exposure to plasma levels exceeding 50 microM may result in a higher incidence of serious non-hematologic toxicity.

Antineoplastic Agents↗
PubMed1990

Metabolism and action of amino acid analog anti-cancer agents.

The preclinical pharmacology, antitumor activity and toxicity of seven of the more important amino acid analogs, with antineoplastic activity, is discussed in this review. Three of these compounds are antagonists of L-glutamine: acivicin, DON and azaserine; and two are analogs of L-aspartic acid: PALA and L-alanosine. All five of these antimetabolites interrupt cellular nucleotide synthesis and thereby halt the formation of DNA and/or RNA in the tumor cell. The remaining two compounds, buthionine sulfoximine and difluoromethylornithine, are inhibitors of glutathione and polyamine synthesis, respectively, with limited intrinsic antitumor activity; however, because of their powerful biochemical actions and their low systemic toxicities, they are being evaluated as chemotherapeutic adjuncts to or modulators of other more toxic antineoplastic agents.

Amino Acids↗
PubMed1990

Levamisole as a therapeutic agent for colorectal carcinoma.

The prognosis of colon cancer patients found to have lymph node involvement at the time of primary surgical resection is guarded, with an overall 5-year survival rate of approximately 33%. The compound 5-fluorouracil (5-FU), an antimetabolite with some clinical activity in patients with metastatic colorectal cancer, has failed to produce a clinically meaningful impact when used as a single agent in the adjuvant setting. Recently, the results of a definitive intergroup trial (Moertel et al., N. Engl. J. Med. 322: 352-358, 1990) confirmed the results of a smaller trial that had suggested a therapeutic benefit from the combination of 5-FU and levamisole (Lev), an anthelminthic with immunomodulatory properties; these results have defined a new standard of care for patients with node-positive colon cancer. In this review, the rationale for using Lev as an adjuvant to 5-FU therapy in colon cancer, the immunologic effects of Lev in preclinical and clinical studies, and the results of clinical trials will be discussed.

Animals↗
PubMed1990

Antimetabolites.

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Animals↗
PubMed1989

Toxicity of levamisole and 5-fluorouracil in human colon carcinoma cells.

The combination of 5-fluorouracil (5-FU) with the immunomodulator levamisole (Lev) has been clinically tested in patients with metastatic colorectal carcinoma and as adjuvant therapy following primary tumor surgery. In some studies in advanced disease, the addition of Lev to 5-FU improved the median duration of response; in the adjuvant setting, the combination was associated with improvement in the disease-free survival. We studied whether Lev was directly toxic to three human colorectal carcinoma cell lines (HCT 116, SNU-C4, and NCI-H630). We also evaluated the toxicity of Lev in combination with 5-FU in these three cell lines. Lev inhibited the growth of all three colorectal cell lines, but only at concentrations two logs above that achieved with a standard 150-mg oral dose of Lev. In cell growth studies, 500 and 1,000 microM Lev increased the toxicity of 5-FU in HCT 116 cells in an additive fashion. In clonogenic assays, continuous exposure to 10 or 100 microM Lev was minimally toxic and did not enhance the lethality associated with a 24-hour exposure to 5-FU in any of the cell lines. Lev alone at 1,000 microM decreased colony formation by 45% in HCT 116 cells. A combination of 1,000 microM Lev with 10 microM 5-FU resulted in a decrease in HCT 116 colony formation from 54% to 6% of control levels. Continuous exposure of NCI-H630 cells to 500 microM Lev decreased colony formation to 76.5% of control levels; when Lev was combined with 50 microM 5-FU, colony formation was decreased from 59.5% to 27.5% of control levels. We conclude that at concentrations achievable with conventional doses of Lev, there was no evidence of direct toxicity in these colorectal cell lines. Furthermore, an additive interaction with 5-FU was evident only at suprapharmacologic doses of Lev.

Clone Cells↗
PubMed1989

Methotrexate and dipyridamole combination chemotherapy based upon inhibition of nucleoside salvage in humans.

We have carried out a clinical trial in 23 patients to determine whether dipyridamole modulates the clinical effect of methotrexate. This trial was based upon in vitro studies which indicate that dipyridamole potentiates the cytotoxic action of methotrexate through inhibition of thymidine salvage. Methotrexate was given as a bolus injection 24 h after initiation of a high dose dipyridamole infusion. The trial was designed so that methotrexate was escalated in individuals until toxicity occurred and then the methotrexate dose resulting in toxicity was repeated without dipyridamole. During the course of this study the methotrexate dose was escalated from 10 to 130 mg/m2. While individual patient tolerance varied, moderate to severe myelosuppression and/or mucositis occurred frequently in patients receiving the combination with methotrexate doses greater than or equal to 60 mg/m2. Ten of 10 patients who experienced moderate or severe toxicity with the combination had significantly less toxicity when treated with methotrexate alone. Dipyridamole did not increase toxicity by an alteration in methotrexate elimination. The potentiation of methotrexate by dipyridamole in these patients suggests that physiological thymidine levels are sufficient to perturb the clinical effects of methotrexate and that thymidine salvage may represent a mechanism for clinical resistance to methotrexate. These results also suggest that a high dose dipyridamole regimen can be used as a pharmacological approach to test the role of nucleoside membrane flux on the clinical action of other standard chemotherapeutic drugs. Phase II studies testing the clinical efficacy of this combination should use a methotrexate dose of 60 mg/m2 with a provision for methotrexate dose escalation based upon individual patient tolerance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Pentostatin in hairy cell leukemia: treatment by the special exception mechanism.

An analysis of the clinical outcomes in 66 patients with hairy cell leukemia treated with pentostatin under the Special Exception mechanism of the Division of Cancer Treatment, National Cancer Institute, between 1983 and 1987 has revealed a favorable balance of risk and benefit. Hematologic parameters and performance status were improved in most patients treated outside the clinical trials mechanism. The treating physicians considered 37 patients (56%) to be complete responders and 15 patients (23%) to be partial responders. Four patients (6%) died while receiving pentostatin. Life-threatening leukopenia (wbc count, less than 1,000/mm3) was reported in 24% of patients, and severe or life-threatening infection occurred in 11%. The experience gained with these patients supplements the information presently being collected from the controlled clinical trials and supports the development of a group C treatment protocol.

Adult↗
PubMed1989

Interaction of deoxyuridine with fluorouracil and dipyridamole in a human colon cancer cell line.

We have reported previously that dipyridamole increases the toxicity of 5-fluorouracil and alters fluorouracil metabolism in HCT 116 cells, producing a selective increase in fluorodeoxyuridine monophosphate (FdUMP) levels by blocking the efflux of fluorodeoxyuridine. Dipyridamole also blocks deoxyuridine efflux and prolongs the intracellular half-life of deoxyuridine monophosphate (dUMP). The significance of the effect of dipyridamole on FdUMP and dUMP levels was explored further. In cell growth experiments, 1-50 microM deoxyuridine enhanced the cytotoxicity of 5 microM fluorouracil in a dose-dependent manner, and greater than or equal to 10 microM deoxyuridine increased the augmentation of fluorouracil toxicity produced by 0.5 microM dipyridamole. The effect of deoxyuridine on [6-3H]fluorouracil metabolism was studied. After 4 hr, 25 microM deoxyuridine increased the amount of [3H]FdUMP formed 2- to 4-fold relative to that of fluorouracil +/- dipyridamole alone. The mechanism by which deoxyuridine increased FdUMP was examined by measuring the distribution of [2'-3H]deoxyuridine metabolites following exposure of 25 microM deoxyuridine +/- 5 microM fluorouracil. Tritium appeared in the FdUMP peak at 4 and 24 hr in cells exposed to fluorouracil and deoxyuridine, indicating that [3H]deoxyribose was transferred to fluorouracil. A large buildup of [3H]dUMP was seen in cells exposed to fluorouracil plus deoxyuridine for 4 and 24 hr compared to exposure to [3H]deoxyuridine alone, suggesting that dUMP may also inhibit catabolism of FdUMP. Since the increased FdUMP levels produced by dipyridamole did not appear to correlate with further depletion of thymidine triphosphate pools, the incorporation of [3H]fluorouracil metabolites into nucleic acids was monitored by cesium sulfate density centrifugation. Fluorouracil-RNA increased as a function of time (1, 2 and 13 pmol/10(6) cells after 4, 8 and 24 hr), but fluorouracil-DNA was detected only after 24 hr (0.5 pmol/10(6) cells). Dipyridamole however, did not appear to alter the pattern of incorporation of fluorouracil into either RNA or DNA. Perturbations of endogenous dUMP levels by fluorouracil and dipyridamole were then studied. In cells exposed to fluorouracil alone, dUMP pools were unchanged from control at 2 hr, but they had increased 9-fold by 4 hr (3362 pmol/10(6) cells). Simultaneous exposure to fluorouracil and dipyridamole resulted in a 1.5-fold (566 pmol/10(6) cells) and 13.6-fold (5049 pmol/10(6) cells) increase over control dUMP levels after 2 and 4 hr respectively. The dUMP pools continued to enlarge through 24 hr. The effect of fluorouracil on DNA fragility was examined.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Survival↗
PubMed1989

Hypersensitivity reactions to deoxycoformycin.

Deoxycoformycin (dCF) is a promising new antineoplastic agent in the treatment of lymphoid malignancies, particularly hairy cell leukemia (HCL). Skin toxicity in the form of a maculopapular eruption has previously been reported but has not clearly been associated with idiosyncratic reactions. We present five cases of dCF-related hypersensitivity reactions in which additional systemic manifestations indicated an allergic etiology. The value of dCF in treating lymphoid neoplasms suggests that further study of the treatment of these reactions is indicated.

Adult↗
PubMed1989

Enhancement of 5-fluorouracil's anticancer activity by dipyridamole.

Although the interaction between FUra and DP in HCT 116 cells is fairly complex, data from other investigators indicate that in cell lines in which inhibition of TS is growth limiting at relatively low concentrations of fluoropyrimidines, DP appears to augment the cytotoxicity of FUra and FdUrd by blocking the salvage of dThd (Miller et al., 1987; Schwartz et al., 1987). The previous in vitro data regarding the ability of DP to modulate the toxicity of fluoropyrimidines was obtained in exponentially growing cells. An additional observation that warrants consideration is a report that the inhibition of nucleoside incorporation by DP changed as a function of time in culture (Zhen et al., 1986). Hepatoma 3924A cells in lag and log phase were highly sensitive to DP with IC50 values for dThd incorporation of 0.2 and 0.32 microM, respectively. In contrast, stationary phase cells were insensitive to DP (IC50 = 38.9 microM). Amphotericin B, an antifungal agent which perturbs cell membranes, restored the sensitivity to DP in stationary cells. Several investigators have presented information on the effect of DP on fluoropyrimidines in normal tissues. Lee and Park (1987) examined the effect of DP on FUra and MTX toxicity in a soft-agar cloning assay against two human cancer cell lines and on pooled normal human bone marrow (CFU-C). DP (1 microM) potentiated the action of both MTX (0.1 microM) and FUra (5 microM) on Hep-2 (epidermoid carcinoma), MCF-7 (breast carcinoma) and CFU-C in medium supplemented with either non-dialyzed or dialyzed serum. Woodcock et al. (1987) incubated gallbladder mucosa, obtained from patients undergoing elective surgery for cholelithiasis, with control medium or varying concentrations of DP for 1 hr, and then exposed the mucosal cells to 2.5 microCi [3H]-FdUrd (2.5 microM). After 1 hr, the uptake of FdUrd into the tissue was inhibited to 49% and 42% of control by 0.1 microM and 1 microM, respectively.

Animals↗
PubMed1989

2'-Deoxycoformycin after failure of alpha-interferon in hairy cell leukemia.

Alpha-interferon (IFN) and 2'-deoxycoformycin (dCF) both exhibit substantial activity in the treatment of hairy cell leukemia (HCL). Anecdotal reports have suggested that patients who failed IFN could achieve durable responses with dCF, although the frequency with which this was said to have occurred was unknown. We reviewed the available data on the responsiveness of HCL to dCF after IFN therapy by analyzing cases reported in the literature and those treated under the Special Exception mechanism of the National Cancer Institute, Division of Cancer Treatment. Of 60 such cases identified there were 22 (37%) "compete responses" and 22 (37%) "partial responses" for a total response rate of 74%. Responses appeared to be durable in many cases, lasting up to 2 years at the time of reporting. dCF is an active agent in HCL both as initial therapy and for the salvage of patients who have failed IFN. The relative activity of these two agents and the optimal strategies for their use are currently under investigation in ongoing clinical trials.

Drug Administration Schedule↗
PubMed1988

Correlates of severe or life-threatening toxic effects from trimetrexate.

Trimetrexate, an investigational antifol, has been associated with marked variability in drug tolerance among patients. The agent is extensively protein bound, and hepatic biotransformation plays a major role in its elimination. In early phase II testing, nine of 15 patients who experienced life-threatening or fatal toxic effects from trimetrexate had albumin levels less than or equal to 3.5 g/dL prior to treatment. This prompted a review of the data base on 272 patients entered in phase I clinical trails. The incidence of severe or life-threatening anemia, leukopenia, neutropenia, thrombocytopenia, mucositis, and hepatic toxic effects during the first course of trimetrexate was analyzed according to dose, schedule, prior treatment, and baseline protein and albumin levels. The schedules using doses given by short infusions of 30-60 minutes daily for 5 days or weekly for 3 weeks were generally associated with higher incidence of toxic effects than the schedules using doses given every other week by short infusions or those using continuous infusion. The occurrence of leukopenia and mucositis was dose related. Patients with baseline albumin levels less than or equal to 3.5 g/dL had higher incidence of all types of severe or life-threatening toxic effects than those with albumin levels greater than or equal to 3.6 g/dL, and the differences were significant for the development of anemia, thrombocytopenia, and mucositis. Similar correlations were noted for pretreatment protein levels less than or equal to 6.0 g/dL. The small cohort of patients with leukemia experienced substantial toxic effects and tended to have low protein and albumin levels. Performance status and prior therapy did not emerge as strong predictors of severe toxic effects in the univariate analysis. Multivariate analysis confirmed that the type of cancer (leukemia vs. solid tumor), dose, schedule, and baseline albumin level were significant and independent predictors of severe and life-threatening toxic effects in the phase I patient population. Multivariate analysis including only patients with solid tumors indicated that albumin level, dose, and schedule remained significant predictors of toxic effects. Since normal liver function as reflected by bilirubin and transaminase values were a requirement for eligibility, the results suggest that albumin and protein levels may provide a more sensitive index of hepatic function. Patients with hypoalbuminemia and hypoproteinemia are at increased risk of experiencing severe or life-threatening toxic effects from trimetrexate and should be treated cautiously.

Adult↗
PubMed1988

Cephalotaxine esters: antileukemic advance or therapeutic failure?

Clinical trials conducted in the People's Republic of China and the United States of the antileukemic efficacy of the cephalotaxine esters are reviewed. Harrington has been incorporated into combination regimens for the treatment of newly diagnosed acute nonlymphocytic leukemia (ANLL) in China, and activity with cephalotaxine esters has also been noted in chronic myelogenous leukemia. While the investigational agent homoharringtonine has shown some activity in the United States in ANLL, investigator interest in the United States has waned because of toxicity and inconvenient schedules. The Chinese trials have used different schedules than have U.S. studies and have been associated with less toxicity. These trials provide new information that may lead to further investigations of the cephalotaxine esters in the United States.

Alkaloids↗