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Biomedical subjects

R L Capizzi

Publications and source records attributed to R L Capizzi.

At least 109 records · Page 6Linked to original sources
PubMed1982

Sequential high-dose cytosine arabinoside and asparaginase in refractory acute leukemia.

The development of resistance to Ara-C by leukemia cells may be a multifactorial process. These include diminished rates of anabolism or increased rate of catabolism to Ara-C, competition for incorporation into DNA by higher pool size of the competing normal metabolite, dCTP and perhaps other mechanisms. Laboratory investigations have shown that cellular resistance to lower doses of Ara-C (LoDAC) may be overcome by a substantial increase in the extracellular concentration (dose-effect). Clinical extrapolation of these observations have shown that high dose Ara-C (HiDAC) is effective in re-inducing remission in patients with acute leukemia who have either failed to enter remission or who relapsed while being treated with LoDAC. Other laboratory investigations indicate significant schedule-dependent synergy between sequential HiDAC and asparaginase. Application of these observations to clinical trial has resulted in a 64% complete remission rate in patients with non-lymphocytic leukemia, including those who were previously treated with LoDAC or who had had an antecedent hematologic disorder. Toxicity from this regimen was not significantly different from those employing LoDAC. These preliminary data in patients with high risk disease would suggest that HiDAC/asparaginase might have significant utility in patients with previously untreated acute non-lymphocytic leukemia.

Animals↗
PubMed1982

Methotrexate cytotoxicity for L5178Y/Asn- lymphoblasts: relationship of dose and duration of exposure to tumor cell viability.

To determine the relative contribution of dose and duration of exposure to methotrexate (MTX) cytotoxicity, suspension cultures of L5178Y/Asn- murine leukemic cells were exposed to 0.1 to 100 microM MTX for 3 to 42 hr. Viability was determined by cloning in soft agar. While there was a linear relationship between dose and MTX cytotoxicity for exposure duration of 3 and 6 hr (r = -0.66), there was a pronounced flattening of this curve at exposure durations of 18 to 42 hr (r = -0.48). Furthermore, there was an excellent correlation (r = -0.85) between MTX cytotoxicity and durations of exposure for 6 to 42 hr (dose range, 1 to 100 microM). Using the linear least-squares method, a best-fit equation for the kinetics of MTX cytotoxicity was determined to be: log viability = 2.25 = 1.76 (log duration) - 0.31 (log dose). In practice, this equation predicts that a 1-log increase in duration of exposure results in almost a 2-log increase in cytotoxicity, whereas a 1-log increase in dose results in only a 0.3-log increase in cytotoxicity. The clinical utility of these data suggest that protracted infusions of lower doses of MTX would be equally as useful as or more useful than short-term high-dose infusions.

Animals↗
PubMed1982

Schedule-dependent synergy and antagonism between high-dose 1-beta-D-arabinofuranosylcytosine and asparaginase in the L5178Y murine leukemia.

The effect of schedule of drug administration on the biochemical and therapeutic effects of the combination of 1-beta-D-arabinofuranosylcytosine (ara-C) and asparaginase was investigated in vivo and in vitro using the murine leukemia L5178Y. Treatment of cells in vitro with either ara-C (10(-6) M) or asparaginase (0.5 IU/ml) for 8 hr resulted in 45 and 24% viability, respectively; simultaneous exposure to both drugs resulted in 25% viability, a subadditive effect. Sequential 8-hr in vitro treatments with asparaginase preceding ara-C or ara-C preceding asparaginase resulted in 43 and 8% viability, respectively, indicating strong schedule dependency. Recovery from drug-induced inhibition of cell growth in vivo suggested an optimal interval of 120 hr. Treatment of leukemic mice with asparaginase, ara-C, or both drugs simultaneously 3 days after inoculation of 10(6) cells resulted in mean survival times of 16, 21, and 18 days, respectively (control mean survival time, 10 days). With a 120-hr interval between the two drugs, treatment with ara-C followed by asparaginase resulted in 20 of 24 sixty-day survivors. In contrast, when asparaginase preceded ara-C, there was a mean survival time of only 23 days with no 60-day survivors. Maximal weight loss with either combination was only 10%. Mechanisms for the pharmacological antagonism include asparaginase-induced decreased cellular uptake and incorporation of ara-C into macromolecules. The apparent synergy is related to the timing of asparaginase treatment, the "optimal therapeutic effect" occurring when sequential asparaginase is administered before the cells recover from the ara-C effect. Since both drugs are probable components of antileukemic combinations, understanding of such drug-drug interactions would optimize clinical therapy.

Animals↗
PubMed1981

Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells.

In a variety of cell culture and in vivo experiments with normal and tumor-bearing animals, the antecedent or simultaneous use of protein synthesis inhibitors with antimetabolites or alkylating agents will significantly attenuate the cytotoxic effects of the latter. The protein synthesis inhibitor asparaginase shares this potential. In murine leukemia L5178Y which is sensitive to both asparaginase and methotrexate (MTX), the prior use of asparaginase or the simultaneous administration of both drugs results in subadditive effects. In tumor-bearing mice, multiple courses of sequential MTX followed by asparaginase cured 55% of the leukemic mice whereas the converse sequence cured none. Partial explanation for this pharmacologic antagonism includes asparaginase-induced decrease in cellular uptake of MTX and delay in cell cycle traverse. It is of importance to recognize such pharmacologic antagonism for the proper design of clinical trials. Studies with human leukemic lymphoblasts suggest that the optimal time interval between asparaginase and a subsequent dose of MTX was 9-10 days. A 24-hour interval between methotrexate and a subsequent dose of asparaginase permits at least an additive therapeutic effect. The repeated use of this 2-day tandem schedule (MTX AsNase) permits the host to tolerate increasingly larger doses of MTX. These larger doses of MTX may have therapeutic benefit for the following reasons: 1) the steep dose-response relationship for MTX, 2) larger doses may overcome "transport-resistant" populations, and 3) larger doses may penetrate pharmacologic sanctuaries such as the blood-brain barrier. Trials of this combination in adults and children with advanced lymphoblastic leukemia, many of whom were previously treated with asparaginase and were refractory to conventional doses of MTX, resulted in complete remissions of 64% and 50%, respectively.

Adult↗
PubMed1981

Kinetics of phototoxicity of Fischer's medium for L5178Y leukemic cells.

The uncontrolled exposure of Fischer's medium to cool white fluorescent (CWF) light or other sources emitting near-ultraviolet or visible light absorbance by riboflavin is a crucial random variable in experiments which utilize L5178Y cells and this medium. The radiation effects of CWF light result in the rapid development of toxic photoproducts in the medium which are cytostatic at lower doses of radiation and cytotoxic at higher doses. After a 24-hr suspension in medium irradiated for 3 or 48 hr, the cloning efficiencies of cells subsequently plated in light-protected medium were 87 and 3%, respectively. The corresponding near-ultraviolet doses for these periods of exposure to CWF light were 0.22 x 10(4) for a 3-hr exposure and 3.47 x 10(4) J/sq m for a 48-hr exposure. Cells incubated in lightly irradiated medium resumed growth at nearly normal rates following a 24- to 48-hr period in which no increase in cell numbers occurred. Exposure of medium containing riboflavin, but not tryptophan or tyrosine, to CWF light also produces toxic medium. Tryptophan enhances riboflavin-induced phototoxicity, whereas tyrosine diminishes this effect. As photosusceptibility of this system is very high, Fischer's medium must be fully protected from all sources of light absorbable by riboflavin.

Animals↗
PubMed1979

Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood.

Two groups of children with refractory acute lymphoblastic leukemia were treated with a regimen of methotrexate (MTX) and asparaginase (Asn'ase) based on studies of the effect of MTX in vitro on human lymphoblasts exposed to Asn'ase. Induction therapy in 12 children produced 4 complete remissions, 3 partial remissions, and 5 failures. Responsiveness to Asn'ase seemed necessary for successful induction with the drug combinations. Maintenance therapy in 18 children produced a median hematologic remission of 31 weeks (range 3-85 weeks). During remission, 2 children developed central nervous system leukemia and 2 died of infection. The mean maximally tolerated dose of MTX was 361 mg/m2. The results of this trial suggest therapeutic synergy in maintenance therapy and the capability of Asn'ase to attenuate MTX toxicity.

Adolescent↗
PubMed1979

High dose cytosine arabinoside (HDARAC) in refractory acute leukemia.

Thirteen leukemic patients with disease refractory to conventional chemotherapy were treated with 1.0 to 7.5 g/m2 of Cytosine Arabinoside (Ara-C) over 29 drug cycles. Drug infusions were spaced at 12-hour intervals; a maximum of four doses was administered over 36 hours. After single dose tolerance had been established, three or four dose cycles were given at 2- to 30-day intervals. There were three partial remissions (PR) and one complete remission (CR) in a treatment group of four patients with AML, five with ALL, two with lymphoma converted to leukemic phase, one CML in blast crisis, and one promyelocytic leukemia. Five of the patients were septic and considered terminally ill at the time of treatment. All other patients had evidence of drug responsiveness. The nadir of the white count occurred from 3 to 12 days after treatment, with subsequent recovery of the peripheral granulocyte count between days 12 and 28. Toxicity included nausea and vomiting (GI symptoms) in twelve patients, central nervous system (CNS) disturbances in eight patients, one episode of inappropriate antidiuretic hormone syndromes (SIADH), one of hyperuricemia, and fever in eleven patients. There was no evidence of hepatic or renal dysfunction. These high doses of Ara-C appear useful for treatment of patients with refractory leukemia. Hospitalization is brief and toxicity acceptable.

Acute Disease↗
PubMed1978

Controlled trial of methotrexate and Bacillus Calmette-Guérin therapy for advanced head and neck cancer.

Thirty-eight patients with advanced, inoperable squamous cell carcinoma of the head and neck were randomized to receive methotrexate alone or methotrexate with Bacillus Calmette-Guérin. The response rates with methotrexate (3 of 19) and methotrexate plus B. Calmette-Guérin (4 of 16) were similar, as was the duration of response and survival of the two groups. The results of in vitro immunological studies of lymphocytes were assessed. Marked weight loss, poor performance status, and distant metastases were the most important prognostic factors. The presence of anergy was significantly correlated with weight loss. This study also indicated that a large tumor burden is a frequent occurrence in advanced head and neck cancer and may account for the lack of efficacy of B. Calmette-Guérin.

B-Lymphocytes↗
PubMed1977

Acute nonlymphocytic leukemia: a delayed complication of Hodgkin's disease therapy: analysis of 109 cases.

The use of combined modality therapy (irradiation and combinations of drugs) in the treatment of Hodgkin's disease has produced a significant improvement in survival, during which most patients lead an active and productive life. The estimated 1% incidence of leukemia in treated Hodgkin's disease patients, however, is greater than would be expected in the general population. There is a vast amount of literature which indicates that alkylating agents, procarbazine and irradiation are leukemogenic and immunosuppressive in animals and man. It is than conceivable that the current intensive treatment programs which use these agents are promoting the development of acute non-lymphocytic leukemia (ANLL). This leukemia has occurred most often in patients whose Hodgkin's disease is poorly controlled and who have received more aggressive therapy. The latent period from the diagnosis of Hodgkin's disease to the diagnosis of leukemia is significantly shorter (p less than .0005) in those patients who have received intensive and near maximal radiotherapy (total nodal irradiation), combination chemotherapy (MOPP or equivalent) or a sequential combination of the two modalities than similar patients who were treated with less than total nodal irradiation and or single agent chemotherapy. The following characteristic features have occurred with sufficient frequency to suggest that the subsequent leukemia is a distinct clinicopathological entity: pancytopenia, megaloblastoid marrow, nucleated red blood cells in the peripheral blood, random chromosomal aberrations of the bone marrow in most patients (94%), and refractoriness to antileukemia therapy (response rate 6.5%) with a very short survival (median one month).

Acute Disease↗
PubMed1977

Renal failure secondary to leukemic infiltration of the kidneys.

Leukemic infiltration of the kidneys is a very rare cause of renal failure. A woman with acute lymphoblastic leukemia presented with nonliguric renal failure and was found to have massively enlarged kidneys. The size of the kidneys was dramatically reduced through the combined effects of local radiation therapy and systemic chemotherapy. Because this rapid shrinkage of the kidneys was associated with improvement in renal function, the uremia was ascribed to leukemic infiltration. As a consequence of rapid tumor lysis in the presence of renal failure, marked hyperphosphatemia and hypocalcemia developed. The literature experience with renal failure secondary to leukemic infiltration of the kidneys is reviewed.

Calcium↗