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Biomedical subjects

H S Friedman

Publications and source records attributed to H S Friedman.

At least 55 records · Page 3Linked to original sources
PubMed1999

Smoothing bandwidth selection for response latency estimation.

Stimulus response latency is the delay between stimulus onset and the evoked modulation in neural activity. A common technique to estimate latencies involves binning the spike arrival times to form a peri-stimulus histogram. This histogram is smoothed using a fixed bandwidth. The estimated latency is the first time following stimulus onset in which the smoothed histogram exceeds the midpoint between the minimum and maximum of the smoothed histogram. We demonstrate that the choice of smoothing bandwidth is critical to the accuracy of this latency estimation technique. We suggest a bootstrap resampling technique for bandwidth selection which results in a robust latency estimate.

Animals↗
PubMed1999

Multiple DNA repair mechanisms and alkylator resistance in the human medulloblastoma cell line D-283 Med (4-HCR).

PURPOSE: We have previously reported preferential repair of DNA interstrand crosslinks in the 4-hydroperoxycyclophosphamide-resistant human medulloblastoma cell line D-283 Med (4-HCR). We now report further studies that explored the potential mechanisms underlying this repair. METHODS: Limiting dilution assays and Western, Southern, and Northern blots were used to compare specific differences between D-283 Med (4-HCR) and its parental line D-283 Med. RESULTS: D-283 Med (4-HCR) was cross-resistant to melphalan and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with O6-alkylguanine-DNA alkyltransferase (AGT) levels of 466+/-164 fmol/mg protein; AGT levels in the parental line, D-283 Med, were 76+/-96 fmol/mg. The increase in AGT activity was not a result of gene amplification. Depleting AGT with O6-benzylguanine partially restored sensitivity to BCNU. Both cell lines were deficient in the human mismatch protein MutLalpha. ERCC4 mRNA and poly(ADP-ribose) polymerase levels were similar in both cell lines, and ERCC1 mRNA levels were 2- to 2.5-fold lower in D-283 Med (4-HCR). Topoisomerase I levels were 2- to 2.5-fold higher in D-283 Med compared with D-283 Med (4-HCR). CONCLUSION: These results, while illustrating the multiple differences between D-283 Med and D-283 Med (4-HCR), do not explain the enhanced DNA interstrand crosslink repair seen in D-283 Med (4-HCR).

Antineoplastic Agents, Alkylating↗
PubMed1999

Modulation of cyclophosphamide activity by O6-alkylguanine-DNA alkyltransferase.

PURPOSE: The human medulloblastoma cell line D283 Med (4-HCR), a line resistant to 4-hydroperoxycyclophosphamide (4-HC), displays enhanced repair of DNA interstrand crosslinks induced by phosphoramide mustard. D283 Med (4-HCR) cells are cross-resistant to 1,3-bis(2-chloroethyl)- -nitrosourea, but partial sensitivity is restored after elevated levels of O6-alkylguanine-DNA alkyltransferase (AGT) are depleted by O6-benzylguanine (O6-BG). Studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) after AGT is depleted by O6-BG. METHODS: Limiting dilution and xenograft studies were conducted to define the activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide with or without O6-BG. RESULTS: The activity of 4-HC and 4-hydroperoxydidechlorocyclophosphamide against D283 Med (4-HCR) was increased after AGT depletion by O6-BG preincubation. Similar studies with Chinese hamster ovary cells, with or without stable transfection with a plasmid expressing the human AGT protein, revealed that the AGT-expressing cells were significantly less sensitive to 4-HC and 4-hydroperoxydidechlorocyclophosphamide. Reaction of DNA with 4-HC, phosphoramide mustard, or acrolein revealed that only 4-HC and acrolein caused a decrease in AGT levels. CONCLUSIONS: We propose that a small but potentially significant part of the cellular toxicity of cyclophosphamide in these cells is due to acrolein, and that this toxicity is abrogated by removal of the acrolein adduct from DNA by AGT.

Animals↗
PubMed1999

Molecular genetic aspects of oligodendrogliomas including analysis by comparative genomic hybridization.

Oligodendroglial neoplasms are a subgroup of gliomas with distinctive morphological characteristics. In the present study we have evaluated a series of these tumors to define their molecular profiles and to determine whether there is a relationship between molecular genetic parameters and histological pattern in this tumor type. Loss of heterozygosity (LOH) for 1p and 19q was seen in 17/23 (74%) well-differentiated oligodendrogliomas, in 18/23 (83%) anaplastic oligodendrogliomas, and in 3/8 (38%) oligoastrocytomas grades II and III. LOH for 17p and/or mutations of the TP53 gene occurred in 14 of these 55 tumors. Only one of the 14 cases with 17p LOH/TP53 gene mutation also had LOH for 1p and 19q, and significant astrocytic elements were seen histologically in the majority of these 14 tumors. LOH for 9p and/or deletion of the CDKN2A gene occurred in 15 of these 55 tumors, and 11 of these cases were among the 24 (42%) anaplastic oligodendrogliomas. Comparative genomic hybridization (CGH) identified the majority of cases with 1p and 19q loss and, in addition, showed frequent loss of chromosomes 4, 14, 15, and 18. These findings demonstrate that oligodendroglial neoplasms usually have loss of 1p and 19q whereas astrocytomas of the progressive type frequently contain mutations of the TP53 gene, and that 9p loss and CDKN2A deletions are associated with progression from well-differentiated to anaplastic oligodendrogliomas.

Adolescent↗
PubMed1999

Topotecan for the treatment of recurrent or progressive central nervous system tumors - a pediatric oncology group phase II study.

Topotecan was studied as a 72 h infusion given every 3 weeks. Treatment began at a dose of 1.0 mg/m2/day and was increased to 1.25 mg/m2/day after the first 6 patients tolerated this higher dose without excessive toxicities. Eighty-eight evaluable children were accrued in 6 strata. There were no complete nor partial responses. Twenty subjects had stable disease (astrocytoma 5/11, malignant glioma 5/13, medulloblastoma 0/12, brain stem tumor 4/19, ependymoma 5/17, and miscellaneous histologies 1/16). Two patients (astrocytoma, ependymoma) completed the maximum 18 topotecan courses. The remaining 68 children developed progressive disease within 2 months. Myelosuppression was the main toxicity. Grade 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 18, 32, 5, and 23 participants, respectively. It was concluded that topotecan as given according to this schedule showed insufficient activity to promote it to frontline protocol usage.

Adult↗
PubMed1999

Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats.

The current study was designed to evaluate the toxicity and activity of Spartaject Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 micromol of intrathecal Spartaject Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 micromol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 micromol x 1, 6.2 micromol x 4 and 4.1 micromol x 4, respectively, against D-456 MG. A single dose of 8.1 micromol of intrathecal Spartaject Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 micromol x 1), 52.3% (2.0 micromol x 4), and 23% (8.1 micromol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.

Animals↗
PubMed1999

Diagnostic markers in paediatric medulloblastoma: a Paediatric Oncology Group Study.

AIMS: We have reviewed immunohistochemically 17 paediatric medulloblastomas in order to determine if correlations exist that might be useful in subclassifying these tumours. METHODS AND RESULTS: The patient group included 11 children who had died (mean survival 13 months) and six still alive (followed for up to 10 years). Ten tumours were diffuse and six were nodular (one biopsy had only perivascular tumour). Of the 10 diffuse tumours, three were desmoplastic: of the six nodular tumours, all six were desmoplastic. All 17 tumours were synaptophysin-reactive: three nodular tumours were glial fibrillary acidic protein (GFAP)-reactive in the nodules (two of three S 100-reactive tumours were also GFAP-reactive). MIB-1 labelling indices (LI) ranged from 5 to 80%. Six tumours exhibited at least 1% LI against Tp53 (Mab D07 and/or Mab 1801). Eight cases were 100% bcl2-reactive with nine cases having an LI <80% ('low labelling'). All nine 'low labelling' bcl2 cases were TP53 non-reactive; all six Tp53-reactive cases were bcl2 100% reactive. Six of 10 patients with diffuse medulloblastomas survived 18 months or less while four of 10 are alive up to 10 years. In contrast, five of six patients with nodular neoplasms died within 48 months of diagnosis with one patient followed up for less than 1 year. CONCLUSIONS: Immunohistochemistry is a useful adjunct in characterizing subsets of paediatric medulloblastomas and confirms that larger co-operative studies may be fruitful in identifying a prognostic utility of a combined histochemical/immunohistochemical analysis on these tumours.

Adolescent↗
PubMed1999

Color filling-in under steady fixation: behavioral demonstration in monkeys and humans.

Color filling-in is a phenomenon in which the color of an object appears to be filled-in by the color of the surrounding field. We have studied the question of whether monkeys perceive color filling-in with near-foveal stimuli under steady fixation. Two monkeys were trained to fixate steadily and to attend to a disk, surrounded by an annulus of the complementary color, in parafoveal vision. Using displays in which the color of the disk was gradually changed to that of the annulus, we trained the animals to signal when they perceived a uniform color field. During the experiment, we introduced a small percentage of trials in which the disk color remained constant, and looked for 'filling-in' responses in these trials. Three human subjects were also tested for comparison. All subjects produced 'filling-in' responses with frequencies that were significantly higher for static disks with blurred borders than for moving disks or disks with sharp borders. This indicates that the monkeys' responses reflected perceptual filling-in, rather than random behavior. The time course of filling-in was similar in monkeys and humans. For the blurred static disks, responses occurred first after 3-4 s of fixation, reaching a probability of 0.2-0.8 by the end of 6 s, depending on the subject.

Adult↗
PubMed1999

Irinotecan therapy in adults with recurrent or progressive malignant glioma.

PURPOSE: To determine the activity, toxicity, and pharmacokinetics of irinotecan (CPT-11, Camptosar; Pharmacia & Upjohn, Kalamazoo, MI) in the treatment of adults with progressive, persistent, or recurrent malignant glioma. PATIENTS AND METHODS: Patients with progressive or recurrent malignant gliomas were enrolled onto this study between October 1996 and August 1997. CPT-11 was given as a 90-minute intravenous (i.v.) infusion at a dose of 125 mg/m2 once weekly for 4 weeks followed by a 2-week rest, which comprised one course. Plasma concentrations of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were determined in a subset of patients. RESULTS: All 60 patients who enrolled (36 males and 24 females) were treated with CPT-11 and all were assessable for toxicity, response, and survival. Pharmacokinetic data were available in 32 patients. Nine patients (15%; 95% confidence interval, 6% to 24%) had a confirmed partial response, and 33 patients (55%) achieved stable disease lasting more than two courses (12 weeks). Toxicity observed during the study was limited to infrequent neutropenia, nausea, vomiting, and diarrhea. CPT-11, SN-38, and SN-38G area under the plasma concentration-time curves through infinite time values in these patients were approximately 40%, 25%, and 25%, respectively, of those determined previously in patients with metastatic colorectal cancer not receiving antiepileptics or chronic dexamethasone treatment. CONCLUSION: Response results document that CPT-11, given with a standard starting dose and treatment schedule, has activity in patients with recurrent malignant glioma. However, the low incidence of severe toxicity and low plasma concentrations of CPT-11 and SN-38 achieved in this patient population suggest that concurrent treatment with anticonvulsants and dexamethasone enhances drug clearance.

Adult↗
PubMed1999

Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group.

PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse. PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle. RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients. CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.

Adult↗
PubMed1999

The effects of erythromycin on the electrocardiogram.

BACKGROUND: Various cardiac electrophysiologic effects have been attributed to erythromycin. During the course of treating a pneumonia patient with IV erythromycin, the conversion of atrial fibrillation to a sinus rhythm, and its subsequent reversal, appeared to be causally related to the introduction and cessation of this antibiotic. OBJECTIVE: This observation suggested the need for studying the changes in the ECG following the use of IV erythromycin in a typical clinical setting. DESIGN: A prospective comparative drug study. SETTING: A university-affiliated teaching hospital. PATIENTS: Nineteen patients being treated for uncomplicated community-acquired pneumonia. INTERVENTION: IV erythromycin, 500 mg, and/or IV cefuroxime, 750 mg, infused in 250 mL of saline over 20 min. In the 11 patients who were receiving both of the antibiotics, cefuroxime was administered immediately before erythromycin was infused. MEASUREMENTS: The 12-lead ECG measurements were obtained before infusion, at 5-min intervals during each infusion, and at 5 and 10 min after the infusions had been completed. All of the ECG complexes and intervals were measured using a software program (Interpretive Cardiograph; Hewlett Packard; Palo Alto, CA). RESULTS: The administration of IV erythromycin increased heart rate and prolonged the corrected QT (QTc) interval. These changes were significant at 15 min of the infusion, and were no longer evident 5 min after the infusion had been stopped. The administration of IV cefuroxime did not produce any ECG changes. CONCLUSIONS: A single, standard dose of IV erythromycin prolongs the QTc interval; therefore, the drug should always be administered as a slow infusion. ECG monitoring should accompany erythromycin therapy in critically ill patients, in patients with electrolyte disorders, or in patients taking other drugs with similar cardiac effects.

Adult↗
PubMed1999

Dosimetry of 131I-labeled 81C6 monoclonal antibody administered into surgically created resection cavities in patients with malignant brain tumors.

UNLABELLED: The objective of this study was to perform the dosimetry of 131I-labeled 81C6 monoclonal antibody (MAb) in patients with recurrent malignant brain tumors, treated by direct injections of MAb into surgically created resection cavities (SCRCs). METHODS: Absorbed dose estimates were performed for nine patients. Dosimetry was performed retrospectively using probe counts (during patient isolation) and whole-body and SPECT images thereafter. Absorbed doses were calculated for the SCRC interface and for regions of interest (ROIs) 1 and 2 cm thick, measured from the margins of cavity interface. Also, mean absorbed doses were calculated for normal brain, liver, spleen, thyroid gland, stomach, bone marrow and whole body. The average residence time for the SCRC was 111 h (65-200h). RESULTS: The average absorbed dose per unit injected activity (range) to the SCRC interface and ROIs 1 and 2 cm thick from the cavity interface were 31.9 (7.8-84.2), 1.9 (0.7-3.6) and 1.0 (0.4-1.8) cGy/MBq, respectively. Average absorbed doses per unit administered activity to brain, liver, spleen, thyroid, stomach, bone marrow and whole body were 0.18, 0.03, 0.08, 0.05, 0.02, 0.02 and 0.01 cGy/MBq, respectively. The high absorbed dose delivered to the SCRC interface may have produced an increase in cavity volume independent of tumor progression. CONCLUSION: At the maximum tolerated dose of 3700 MBq 131I-labeled 81C6 MAb, the absorbed doses to the SCRC interface and ROIs of 1 and 2 cm thickness were estimated to be 1180, 71 and 39 Gy, respectively. The estimated average absorbed dose to the brain was 6.5 Gy. There was no neurological toxicity and minimal hematologic toxicity at this maximum tolerated administration level.

Brain Neoplasms↗
PubMed1999

Treatment of neoplastic meningitis with intrathecal temozolomide.

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (i.t.) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct i.t. use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an i.t. agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 micromol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the i.t. administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.

Animals↗
PubMed1999

Verapamil prolongs atrial fibrillation by evoking an intense sympathetic neurohumoral effect.

BACKGROUND: Verapamil is an effective drug to slow ventricular rate in atrial fibrillation (AF). Clinically, however, i.v. verapamil enhances AF despite experimental evidence suggesting favorable effects of the drug on AF-induced electrical remodeling of the atria. METHODS AND RESULTS: To clarify this controversy, i.v. verapamil's effects were determined in 41 anesthetized dogs, including 6 after beta-blockade. Intravenous verapamil (0.20 mg/kg, bolus, and 0.20 mg/kg/h, infusion) increased the duration of AF (induced by a single extrastimulus), from 19 +/- 6 to 130 +/- 24 s, P < 0.001, and slowed its ventricular response, from 246 +/- 25 to 110 +/- 15 min-1, P < 0.001. Mean aortic pressure, P = 0.002, and systemic vascular resistance, P < 0.035, decreased, and mean right atrial pressure increased, P < 0.001. Plasma norepinephrine concentration increased by 502 +/- 83 pg/mL, P < 0.001, plasma epinephrine concentration by 804 +/- 206 pg/mL, P = 0.002, and plasma total catecholamine concentration by 1606 +/- 366 pg/mL, P = 0.001. Prolongation of AF was related to an increase in mean right atrial pressure, R = 0.49, P = 0.014, right atrial wall tension, R = 0.45, P = 0.044, and plasma norepinephrine concentration, R = 0.83, P < 0.001, with plasma norepinephrine concentration remaining as an independent predictor of AF lengthening on multivariable analysis. In the presence of beta-blockade, verapamil produced comparable or more exaggerated hemodynamic effects, but it did not promote AF. CONCLUSION: The prolongation of AF by verapamil can be related directly to the intense sympathetic neurohumoral effect that occurs following the drug's administration.

Animals↗
PubMed1999

Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1.

The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.

ADP Ribose Transferases↗
PubMed1999

Lack of evidence for a polymorphism at codon 160 of human O6-alkylguanine-DNA alkyltransferase gene in normal tissue and cancer.

O6-benzylguanine (BG) is a potent, specific inactivator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which enhances sensitivity to nitrosoureas in cells and tumor-bearing animals. BG is presently undergoing clinical trials for development as an agent to enhance the therapeutic index of alkylating agent chemotherapy. It has been reported that a polymorphism exists in the human agt gene, with about 15% of the Japanese population having arginine at codon 160 instead of glycine on the polypeptide (Y. Imai et al., Carcinogenesis, 16: 2441-2445, 1995). The resultant mutant AGT protein is equally effective against both methylated DNA as compared with wild type protein. However, this mutant AGT protein was less sensitive to inactivation by BG with a 20-fold increase in the ED50 value. This observation raised the possibility that a subpopulation of patients may be resistant to BG due to a single base change. We have demonstrated that this alteration also reduces the sensitivity to O6-benzyl-8-oxoguanine, an equally potent, yet much longer-lived human metabolite of BG. To test the possibility that this germ-line mutation of the agt gene might explain resistance to BG and O6-benzyl-8-oxoguanine of patients on our Phase I clinical trials, we evaluated the DNA from lymphocytes of 18 patients. The G160R mutation was not found in any of the 18 patients. To determine the frequency of this mutation in the United States population, DNA from 181 healthy individuals were investigated and, again, the mutation was not observed in this cohort. Therefore, if the mutation exists, it is in statistically <1.6% of the United States noncancerous population. To investigate the possibility that this mutation might be somatic, we evaluated genomic DNA samples from 94 human primary cancers of four different histological subtypes (brain, colon, esophageal, and head and neck). Again, none were found to have the G160R mutation.

Animals↗