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H S Friedman

Publications and source records attributed to H S Friedman.

At least 19 recordsLinked to original sources
PubMed2001

Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.

Antibodies, Monoclonal↗
PubMed2001

Inactivation of O6-alkylguanine-DNA alkyltransferase by 8-substituted O6-benzylguanine analogs in mice.

PURPOSE: The purpose of this study was to determine the usefulness of various 8-substituted O6-benzylguanine (BG) analogs as modulators of the DNA repair protein. O6-alkylguanine-DNA alkyltransferase (AGT). More specifically, the degree of inactivation of AGT in mouse brain, liver, kidney and tumor by O6-benzyl-8-oxoguanine (8-oxoBG), 8-aza-O6-benzylguanine (8-azaBG), O6-benzyl-8-bromoguanine (8-bromoBG) and O6-benzyl-8-trifluoromethylguanine (8-tfmBG) was compared to inactivation by BG, a modulator in phase II clinical trials. BG is converted rapidly to 8-oxoBG in rodents, monkeys and humans. It was reasoned that 8-substituted analogs of BG would exhibit different pharmacological properties compared to BG which could influence tissue bioavailability and, thus, the extent of AGT inactivation in vivo. We compared the tissue distribution of these agents and AGT activity following administration of the 8-substituted analogs. MATERIALS AND METHODS: At various time points up to 24 h after i.p. administration of the BG analogs, tissues (i.e. brain, liver, kidney), A549 lung tumor xenografts (i.p.) or D456 brain tumor xenografts (i.c.) were harvested from athymic nude mice for AGT analysis. AGT activity was quantified in tissue extracts using a biochemical assay with [3H]methylated DNA as a substrate. In addition, concentrations of BG and 8-oxoBG were determined by HPLC with fluorescence detection in mouse tissues following administration of drug. RESULTS: Each of the 8-substituted analogs of BG demonstrated variable AGT inactivation capabilities that were comparable to or better than those of BG especially in kidney and brain tissues. There was a more pronounced depletion of AGT inactivation in brain and D456 brain tumor xenografts following administration of BG compared to 8-oxoBG that could be explained by a much greater concentration of AGT-inactivating drug (BG plus the metabolite 8-oxoBG for mice treated with BG versus 8-oxoBG for mice treated with 8-oxoBG) present in these tissues. The AUCs for brain, kidney and liver were 3.2, 6.9 and 1 1.8 times greater for BG than for 8-oxoBG. CONCLUSIONS: 8-substituted analogs of BG possess unique AGT-inactivation profiles in vivo that are different from that of BG. The AGT-inhibitory activities of BG and its major metabolite, 8-oxoBG, are related to tissue disposition of both drugs.

Animals↗
PubMed2001

Acyl derivatives of demethylpenclomedine, an antitumor-active, non-neurotoxic metabolites of penclomedine.

PURPOSE: The purpose of this investigation was to compare the antitumor activities of a series of acyl derivatives of 4-demethylpenclomedine (DM-PEN), the major plasma metabolite of penclomedine (PEN) observed to be an active antitumor agent in vivo and non-neurotoxic in a rat model with that of DM-PEN. METHODS: Acyl derivatives were prepared from DM-PEN and evaluated in vivo against human MX-1 breast tumor xenografts implanted subcutaneously (s.c.) or intracerebrally (i.c.). Several derivatives were also evaluated against other human tumor xenografts and murine P388 leukemia cell lines. RESULTS: Several of the acyl derivatives were found to be superior to DM-PEN against MX-1, human ZR-75-1 breast tumor, human U251 CNS tumor and the P388 leukemia parent cell line and lines resistant to cyclophosphamide and carmustine. 4-Demethyl-4-methoxyacetylpenclomedine showed inferior activity to current clinical brain tumor drugs against a glioma cell line, superior activity to temozolomide and procarbazine against the derived mismatch repair-deficient cell line, and superior activity to cyclophosphamide and carmustine but inferior activity to temozolomide against two ependymoma cell lines, all of which were implanted s.c. CONCLUSION: Proposed mechanisms of activation and action of DM-PEN and the acyl derivatives support the potential clinical superiority of the acyl derivatives.

Animals↗
PubMed2001

Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice.

PURPOSE: Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice. METHODS: Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR)) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals. RESULTS: Karenitecin produced statistically significant (P < or = 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90+ days in D-212 MG and D-341 MED. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). CONCLUSION: These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors.

Animals↗
PubMed2001

Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyla-2-hydroxyl) ethylamino-12,13-dihydro-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]] against pediatric and adult central nervous system tumor xenografts.

PURPOSE: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts. METHODS: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)]. RESULTS: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001). CONCLUSION: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent.

Adult↗
PubMed2001

Activity of irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice.

PURPOSE: This study was conducted to define the activity of irofulven in the treatment of a series of xenografts derived from human glioblastoma multiforme growing subcutaneously and intracranially in athymic nude mice. METHODS: Athymic mice bearing subcutaneous or intracranial tumors were treated with irofulven at a 10% lethal dose with responses compared to tumor-bearing mice treated with drug vehicle. RESULTS: Irofulven was active against all tumor lines tested with growth delays ranging from 5.6 to 81.6 days (all values statistically significant, P < or = 0.001). Irofulven also produced a statistically significant (P < or = 0.001) increase in the median survival of mice bearing D-456 intracranial xenografts with a 162% increase in median survival. CONCLUSIONS: Irofulven is active in a spectrum of human glioblastoma multiforme-derived xenografts and evaluation in patients with this neoplasm is warranted.

Animals↗
PubMed2001

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Adult↗
PubMed2001

Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers.

UNLABELLED: Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [(18)F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncologic probe in comparison with several other closely related molecules. METHODS: FCH, [(18)F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [(18)F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [(18)F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [(18)F]fluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and [methyl-(14)C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. RESULTS: FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. CONCLUSION: The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.

Adult↗
PubMed2000

Phase I trial results of iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with newly diagnosed malignant gliomas.

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine-131 ((131)I)-labeled 81C6 antitenascin monoclonal antibody (mAb) administered clinically into surgically created resection cavities (SCRCs) in malignant glioma patients and to identify any objective responses with this treatment. PATIENTS AND METHODS: In this phase I trial, newly diagnosed patients with malignant gliomas with no prior external-beam therapy or chemotherapy were treated with a single injection of (131)I-labeled 81C6 through a Rickham reservoir into the resection cavity. The initial dose was 20 mCi and escalation was in 20-mCi increments. Patients were observed for toxicity and response until death or for a minimum of 1 year after treatment. RESULTS: We treated 42 patients with (131)I-labeled 81C6 mAb in administered doses up to 180 mCi. Dose-limiting toxicity was observed at doses greater than 120 mCi and consisted of delayed neurotoxicity. None of the patients developed major hematologic toxicity. Median survival for patients with glioblastoma multiforme and for all patients was 69 and 79 weeks, respectively. CONCLUSION: The MTD for administration of (131)I-labeled 81C6 into the SCRC of newly diagnosed patients with no prior radiation therapy or chemotherapy was 120 mCi. Dose-limiting toxicity was delayed neurologic toxicity. We are encouraged by the survival and toxicity and by the low 2.5% prevalence of debulking surgery for symptomatic radiation necrosis.

Adult↗
PubMed2000

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Adult↗
PubMed2000

Coding of border ownership in monkey visual cortex.

Areas V1 and V2 of the visual cortex have traditionally been conceived as stages of local feature representations. We investigated whether neural responses carry information about how local features belong to objects. Single-cell activity was recorded in areas V1, V2, and V4 of awake behaving monkeys. Displays were used in which the same local feature (contrast edge or line) could be presented as part of different figures. For example, the same light-dark edge could be the left side of a dark square or the right side of a light square. Each display was also presented with reversed contrast. We found significant modulation of responses as a function of the side of the figure in >50% of neurons of V2 and V4 and in 18% of neurons of the top layers of V1. Thus, besides the local contrast border information, neurons were found to encode the side to which the border belongs ("border ownership coding"). A majority of these neurons coded border ownership and the local polarity of luminance-chromaticity contrast. The others were insensitive to contrast polarity. Another 20% of the neurons of V2 and V4, and 48% of top layer V1, coded local contrast polarity, but not border ownership. The border ownership-related response differences emerged soon (<25 msec) after the response onset. In V2 and V4, the differences were found to be nearly independent of figure size up to the limit set by the size of our display (21 degrees ). Displays that differed only far outside the conventional receptive field could produce markedly different responses. When tested with more complex displays in which figure-ground cues were varied, some neurons produced invariant border ownership signals, others failed to signal border ownership for some of the displays, but neurons that reversed signals were rare. The influence of visual stimulation far from the receptive field center indicates mechanisms of global context integration. The short latencies and incomplete cue invariance suggest that the border-ownership effect is generated within the visual cortex rather than projected down from higher levels.

Animals↗
PubMed2000

Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors.

The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.

Animals↗
PubMed2000

Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy.

PURPOSE: The objective of this study was to perform the dosimetry and evaluate the dose-response relationships in newly diagnosed patients with malignant brain tumors treated by direct injections of (131)I-labeled 81C6 monoclonal antibody (MAb) into surgically created resection cavities (SCRCs). METHODS AND MATERIALS: Absorbed doses to the 2-cm-thick shell as measured from the margins of the resection cavity interface were estimated for 42 patients with primary brain tumors. MR images were used to assess the enhanced-rim volume as a function of time after radiolabeled MAb therapy. Biopsy samples were obtained from 15 patients and 1 autopsy. RESULTS: The average absorbed dose [range] to the 2-cm shell region was 32 [3-59] Gy. For the endpoint of minimal time to MR contrast enhancement, the optimal absorbed dose and initial dose-rate were 43 +/- 16 Gy and 0. 41 +/- 0.10 Gy/h, respectively. There was a correlation between the absorbed dose and dose rate to the shell region and biopsy outcome (tumor recurrence, radionecrosis, and tumor recurrence and/or radionecrosis). In this Phase I study, the maximum tolerated dose (MTD) was 120 mCi. At this MTD, the estimated average absorbed dose and initial dose rate to the 2-cm shell were 41 [9-89] Gy and 0.51 [0.24-1.13] Gy/h, respectively. These values are in agreement with the optimal values based on the time to MR lesion rim enhancement. CONCLUSIONS: The average absorbed dose to the 2-cm shell region varied considerably and mainly depended on cavity volume. In future clinical trials, the administered activity of (131)I-labeled 81C6 MAb may be adjusted based on cavity volume in order to deliver the optimal absorbed dose of 43 Gy rather than giving a fixed administered activity.

Antibodies, Monoclonal↗
PubMed2000

Schedule-dependent activity of irinotecan plus BCNU against malignant glioma xenografts.

PURPOSE: To further evaluate the activity of irinotecan (CPT-11) plus 1,3-bis-(chloroethyl)-1-nitrosourea (BCNU) in the treatment of central nervous system tumor-derived xenografts in athymic nude mice. METHODS: We report studies evaluating the schedule-dependence of this regimen in the treatment of the malignant glioma xenograft D-54 MG. RESULTS: The combination of BCNU and CPT-11 showed the highest enhancement index (2.0-3.3) when BCNU was given on day 1 and CPT-11 was given on days 1-5 and 8-12. Delay of CPT-11 administration to day 3 or day 5 substantially decreased activity with enhancement indices of 1.6-1.8 and 0.6-1.0, respectively. Delay of BCNU administration to day 8 also reduced the CPT-11 activity with enhancement indices of 1.2-1.4. CONCLUSIONS: These results suggest that the presence of a BCNU-induced adduct or possibly crosslink prior to administration of CPT-11 is critical for enhanced activity. Although the mechanism of this enhancement is not currently known, a phase I trial of CPT-11 plus BCNU for adults with recurrent malignant glioma based on these results is in progress.

Animals↗
PubMed2000

O6-benzylguanine-mediated enhancement of nitrosourea activity in Mer- central nervous system tumor xenografts--implications for clinical trials.

PURPOSE: To evaluate the role of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine (O6-BG) in the treatment of both Mer+ and Mer- tumors. METHODS: The effect of pretreatment with O6-BG on the activity of BCNU against Mer- human central nervous tumor xenografts D-54 MG and D-245 MG was evaluated in athymic nude mice. RESULTS: BCNU (1.0 LD10; dose lethal to 10% of treated animals) produced growth delays of 8.9 days and 7.5 days and tumor regressions in six of ten and one of nine animals against D-54 MG, which was derived from a human malignant glioma xenograft. Dose reduction of BCNU to 0.38 LD10 eliminated antitumor activity. The combination of BCNU (0.38 LD10) plus O6-BG produced growth delays of 8.8 days and 7.9 days, with tumor regressions in four of ten and two of nine animals, respectively. BCNU (1.0 LD10) produced a growth delay of 49.8 days and ten of ten tumor regressions against D-245 MG, which was derived from a glioblastoma multiforme. BCNU (0.38 LD10) produced a growth delay of 19.4 days, with nine of ten tumor regressions. The combination of BCNU (0.38 LD10) plus O6-BG produced a growth delay of 65.7 days and seven of eight tumor regressions. CONCLUSION: These results suggest that the combination of BCNU plus O6-BG may be a rational intervention for both Mer+ as well as Mer- tumors.

Animals↗
PubMed2000

Characterization of chromosome 17 abnormalities in medulloblastomas.

Loss of portions of chromosome 17p, usually through the formation of i(17qp) is a well-known finding in medulloblastomas. Loss of heterozygosity (LOH) studies, however, occasionally demonstrate loss of the more distal portions of 17p, a pattern which is more consistent with a terminal deletion. Here we use a combination of routine karyotyping, fluorescence in situ hybridization (FISH) and LOH studies on four medulloblastoma cell lines and one xenograft to demonstrate the spectrum of chromosome 17 abnormalities which occur in these tumors. Cell line D-556 Med showed a typical dicentric i(17q) and cell line D-721 Med showed two normal copies of chromosome 17 by all methods. Cell line D-425 Med showed loss of terminal 17p by LOH, while the karyotype showed what appeared to be an i(17q). FISH and chromosome 17 painting, however, demonstrated that the abnormal chromosome 17 was actually formed through an unbalanced translocation involving two copies of chromosome 17, with breakpoints at p12 and q11-1, an explanation which reconciled the cytogenetic and LOH findings. Cell line D 581 Med had a terminal deletion at 17p11.2. The finding of two cells with i(17q) in this case by interphase FISH suggests that the terminal deletion arose from breakage of an i(17q). Finally, xenograft D 690 Med showed LOH for regions distal to 17p12, whereas karyotyping, FISH using probes on 17p, and chromosome 17 painting showed two intact copies of chromosome 17. This pattern can be explained by homologous recombination. These data support the concept that the critical deletion of 17p can occur through a variety of mechanisms in the medulloblastoma. The losses may occur through typical i(17q), as well as other mechanisms such as terminal deletions, possibly through breakage of i(17q), unbalanced translocations and homologous recombination.

Adolescent↗