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Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 253 records · Page 14Linked to original sources
PubMed1980

Thymidine as a chemotherapeutic agent: sensitivity of normal human marrow, peripheral blood T cells, and acute nonlymphocytic leukemia.

Normal marrow granulocyte (CFU-GM) and peripheral blood T-lymphocyte (CFU-TL) colony-forming cells were studied for their sensitivity to high concentrations of thymidine (dThd) and compared to leukemic CFU from patients with acute nonlymphocytic leukemia (ANLL). The sensitivity of two ANLL cell lines was also assessed. dThd was toxic to both CFU-GM and CFU-TL at concentrations above 10(-5) M when cultured under conditions where dThd exposure was analogous to that used in clinical trials. There was little variation in the fractional colony survival between marrow samples, and the sensitivity of CFU-GM closely approximated that of CFU-TL. Thymine was not toxic at up to 10(-3) M. In liquid culture, T cells in G0 at the start of exposure were able to proliferate in the presence of 10(-3) M dThd, whereas T cells already proliferating in response to phytohemagglutinin (PHA) at the start of dThd exposure were killed. Leukemic CFU demonstrated marked variability in dThd sensitivity; blasts from some patients were resistant to dThd, while others were greater than 100-fold more sensitive than normal CFU-GM.

Acute Disease↗
PubMed1980

Thymidine as a chemotherapeutic agent: pharmacologic, cytokinetic, and biochemical studies in a patient with T-cell acute lymphocytic leukemia.

Biochemical studies suggested that leukemia T-cells have low levels of TTP-catabolizing enzyme activity and are uniquely sensitive to thymidine (dThd). A child with T-cell acute lymphocytic leukemia (ALL), whose peripheral blood lymphoblasts manifested very low TTP catabolic capacity, was treated with 75 g dThd/m2/day by constant iv infusion for two courses of 5 and 8 days. The dThd caused an initial accumulation of peripheral blood blasts in S-phase at the expense of cells in G1, followed by a rapid reversal of this pattern consistent with a block in late G1 and/or early S. Concurrently, a prompt reduction of blasts was found in the peripheral blood. However, dThd treatment neither decreased the number of lymphoblasts in the cerebrospinal fluid (CSF) nor cleared the marrow. No major toxicity was observed, but the effect of dThd on normal marrow elements could not be evaluated in this patient. Blood concentrations of dThd were 1.4-3.0 mM, and concentrations of thymine were in the same range; beta half-life for dThd was 48 minutes. Steady-state CSF dThd was 9% of the simultaneous serum level. Clearance measurements demonstrated that catabolism of dThd was saturated and that renal clearance was a major determinant of total body clearance during high-dose dThd infusion. A good correlation was found between biochemical and cytokinetic parameters and response to dThd for the peripheral blood lymphoblasts. However, dThd did not produce a useful remission in this case of T-cell ALL.

Antineoplastic Agents↗
PubMed1980

Simultaneous liquid chromatography of 5-fluorouracil, uridine, hypoxanthine, xanthine, uric acid, allopurinol, and oxipurinol in plasma.

A reversed-phase "high-pressure" liquid-chromatographic method is described for simultaneous analysis for 5-fluorouracil, uridine, hypoxanthine, xanthine, uric acid, allopurinol, and oxipurinol. Separation was optimal with phosphate buffer (50 mmol/L, pH 4.60) as eluent. A simple acid extraction procedure yielded quantitative recoveries and permitted adequate separation for interfering peaks. Compounds were identified by their retention times, absorbance ratios, co-elution with standards, and enzymatic shifts. With a computerized integrator we quantitated these compounds in widely varying concentrations with a single injection. The limit of sensitivity was 0.1 mumol/L for the compounds studied. This method was applied to determine mean values for those compounds in normal human plasma. They are (in mumol/L): uric acid 276 (SD 55), hypoxanthine 0.46 (SD 0.21), xanthine 0.40 (SD 0.27), and uridine 4.50 (SD 1.70). Erythrocytes and platelets can continue to release hypoxanthine and xanthine into plasma or serum after a blood specimen has been drawn. We believe this explains the higher values previously reported for hypoxanthine and xanthine in serum.

Allopurinol↗
PubMed1980

Antitumor activity of L-canavanine against L1210 murine leukemia.

We have made a preliminary assessment of the antitumor activity of the arginine analog, L-canavanine, in leukemic mice. This analog is known to substitute for arginine in protein biosynthesis in many prokaryotic and eukaryotic systems. Previous studies with cells grown in vitro indicated that canavanine caused a marked inhibition of DNA synthesis and viability. The system used in the present study was C57BL/6 x DBA/2 F mice bearing L1210 leukemic cells. Following an i.v. injection of 10 mg canavanine, the t1/2 beta of canavanine in the serum was estimated at 16 min. This finding suggested that frequent injections of high doses of canavanine would be required for an effect on tumor cell proliferation. DNA synthesis by the L1210 cells, assayed by [3H]thymidine incorporation, fell to 9% of the control value after 12 hourly i.p. injections of canavanine (20 mg each). A constant s.c. infusion of 20 mg/hr for 24 hr caused an 86% inhibition of DNA synthesis. The antitumor activity of canavanine was tested against L1210, using a 24-hr infusion schedule with treatment starting 24 hr after i.p. inoculation of 10(5) cells. An optimal dose of 18 g/kg body weight produced a median increased lifespan of 44% (p less than 0.005). These results suggest that L-canavanine may be useful as an antitumor agent.

Animals↗
PubMed1979

Effect of probenecid on cerebrospinal fluid methotrexate kinetics.

The effect of probenecid (PBC) on methotrexate (MTX) kinetics in the cerebrospinal fluid (CSF) and serum was studied in 4 patients on high-dose MTX with leucovorin rescue to determine whether addition of PBC could prolong effective CSF MTX levels. Each patient received 2 courses of MTX, 1 with and 1 without PBC. PBC caused a 2.8 to 4.2-fold increase in CSF MTX concentrations but failed to prolong the CSF half-life (1 1/2). PBC prolonged the initial MTX elimination t 1/2 in the blood from 2.7 to 4.1 hr, but had little effect on subsequent t 1/2s. No effect of MTX on PBC clearance was detected. Our data suggest that in man PBC in concentrations that were high enough to inhibit the renal clearance of MTX failed to alter the clearance of MTX from the CSF when both drugs were administered systemically.

Adult↗
PubMed1979

Cytokinetic comparison of thymidine and leucovorin rescue of marrow in humans after exposure to high-dose methotrexate.

The cytokinetics of marrow recovery were compared in patients receiving a standard exposure to high-dose methotrexate followed by either thymidine rescue, leucovorin rescue at the doses used in most clinical protocols (10 mg/sq m every 6 hr), or leucovorin rescue at a 5-fold higher dose rate (50 mg/sq m every 6 hr). Thymidine rescue initiated a prompt recovery of DNA synthesis, as detected by [3H]deoxycytidine incorporation, and progression of cells through the cell cycle monitored by flow cytometry, even in the presence of methotrexate levels that prevented initiation of rescue by the lower doses of leucovorin. Dose dependency for leucovorin in vivo in humans was suggested by the observation that the higher leucovorin dose rate was successful in initiating recue within the first 24 hr, whereas the lower dose was not. Recovery of DNA synthesis is more rapid and/or complete with thymidine rescue than with either dose of leucovorin. Thymidine rescue was accomplished without requirement for purines over and above those present in plasma. These results suggest that the kinetics of marrow recovery is quite different for thymidine and leucovorin rescue.

Bone Marrow↗
PubMed1979

Activity of thymidine as a chemotherapeutic agent against human tumor xenografts in nude mice.

The chemotherapeutic activity of thymidine (dThd) was tested against four human tumor xenografts growing in nude mice, including a melanoma, an oat cell carcinoma of the lung, a colon carcinoma, and a breast carcinoma. Tumor-bearing mice were given an infusion of dThd (1 g/kg/day) s.c. for 72 hr each week for three weeks. Tumor growth in the treated mice was compared to that in randomized concurrent control mice infused with media alone. A significant effect was found only for the melanoma, and it was cytostatic rather than cytotoxic. Even when melanomas of very small initial volume were treated, there were no complete regressions, and tumor growth resumed when dThd treatment was stopped. In culture, sustained dThd concentrations of greater than 3.2 mM were required to cause death of the melanoma cells; in the mice the dThd level during infusion ranged from 1 to 5 mM. This exposure to dThd, although failing to produce a tumor response, did produce significant toxicity in the nude mice in the form of myelosuppression and leukopenia. Flow cytometric analysis of marrow cells during the dThd infusion showed an accumulation of cells in S phase, but proliferation was not completely halted since cells with G2-M content of DNA were present in the marrow even after 72 hr of dThd exposure. This study failed to demonstrate a therapeutically useful effect of dThd on these tumors.

Animals↗
PubMed1978

Thymidine rescue of high-dose methotrexate in humans.

Thymidine rescue was administered following 63 courses of high-dose methotrexate in 20 patients. In the first part of this study, the methotrexate was given as a 24-hr infusion and the dose was escalated from 0.14 to 8.54 g/sq m; in the second part, methotrexate was infused to maintain a serum concentration of 15 micrometer for 30, 36, or 40 hr. Thymidine rescue was started immediately after the end of the methotrexate infusions, and consisted of 8 g/sq m/day for 3 days or until serum methotrexate was below a toxic level. Mucositis and myelosuppression were the major toxicities. Neither was dose related. Serum methotrexate levels were proportional to the logarithm of the methotrexate dose. There was a mean 6-fold increase in thymidine concentration during rescue. However, thymidine levels prior to and during rescue were not related to the incidence of subsequent toxicity. Recovery of DNA synthesis in bone marrow cells was evident by nucleoside precursor incorporation at 24 hr after the start of rescue. Two of 16 evaluable patients achieved partial responses. This study indicates that thymidine is an effective rescue agent for high-dose methotrexate in humans.

Adult↗
PubMed1976

Circulating immunoglobulin complexes in Wegener's granulomatosis.

Two cases of Wegener's granulomatosis are reported in which circulating immunoglobulin complexes detected during the active phase of the disease disappeared during induction of remissions of active pulmonary and renal disease by immunosuppressive agents. Elevated antiglobulin activity, urinary immunoglobulin L-chain concentration and evidence of activated coagulation mechanisms were also present during active disease, and returned toward normal with treatment. Studies showed that the serum complexes did not contain deoxyribonucleic acid (DNA) and demonstrated their immunoglobulin nature. Serum complement concentrations were normal, and no cryoglobulins were present. Immunofluorescent staining and electron microscopy of the kidney biopsy specimen of one patient showed marked fibrin deposition but no immunoglobulin or antigen-antibody deposits. Although the role of circulating immunoglobulin complexes in the pathogenesis of Wegener's granulomatosis remains uncertain, serial changes in the described parameters may provide an objective guide to activity of the disease and its response to treatment.

Adult↗
PubMed1975

Defects in cell-mediated immunity during growth of a syngeneic simian virus-induced tumor.

Four assays of tumor-specific cell-mediated immunity were compared during growth of a syngeneic Simian-virus-40-induced tumor, mKSA. Major differences were found in immunity detected by the tumor neutralization test (the Winn test), direct tumor challenge, the microcytotoxicity assay and the -51chromium-release lymphocytotoxicity assay. Progressive growth of the neoplasm followed by loss of immunity (the eclipse phenomenon) was documented with the Winn test. It was established that this eclipse phenomenon represented a lesion in the T-cell system of tumor-bearing hosts. This lesion was found to be specific and unrelated to anatomic tumor location. The ability to produce graft-versus-host reactions, and the ability to respond to mitogens, were found to be generally intact in tumor-bearing animals. Cells capable of recognizing mKSA tumor antigens and reconstituting an immune response following surgical removal of tumor or upon transfer to normal mice were found in the spleens of mice bearing advanced tumors. No suppressor cells that might account for the eclipse phenomenon could be demonstrated. Tumor-bearer serum did not block neutralizing activity of immune spleen cells in the Winn test, and immune cells were capable of neutralizing tumor even in tumor-bearing hosts. The possibility that the lesion is intrinsic to T-cell precursors of effector cells is discussed.

Animals↗
PubMedDate not supplied

Rapid superselective high-dose cisplatin infusion for advanced head and neck malignancies.

Advances in vascular radiology techniques for superselective arterial infusions and methods to overcome systemic toxicity from high-dose cisplatin chemotherapy encouraged us to reevaluate the effects of rapid regional cisplatin infusion for patients with head and neck malignancies. Twenty patients (17 carcinomas, three sarcomas) received high-dose cisplatin (100-200 mg/m2) by this method. Fifteen of the 17 patients with upper aerodigestive tract carcinoma are part of an ongoing phase I dose escalation of cisplatin with sodium thiosulfate neutralization. Three additional patients with sarcomas were treated with intra-arterial (IA) cisplatin and systemic Adriamycin. Fifty-three IA infusions were performed without any complications. Only minimal toxicity related to the chemotherapy was observed. The overall response rate for previously untreated patients was nine of 10 (90%) [complete response (CR) 67%; partial response (PR) 33%]. The response rate for patients with recurrent disease was five of eight (63%) (CR 20%, PR 80%). The average length of follow-up is 9.5 months and the actuarial survival rate is 56%. Superselective rapid infusion of high-dose cisplatin for patients with advanced head and neck malignancies is feasible, relatively nontoxic, and may have important applications in multimodality therapy, particularly for patients with bulky primary disease.

Antidotes↗