PubMed Health⌕ Search

Biomedical subjects

S Weitman

Publications and source records attributed to S Weitman.

At least 19 recordsLinked to original sources
PubMed2001

Biodegradable block copolymers for delivery of proteins and water-insoluble drugs.

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGel's inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

Drug Delivery Systems↗
PubMed2001

A phase I study of cranial radiation therapy with concomitant continuous infusion paclitaxel in children with brain tumors.

BACKGROUND: The prognosis of children with high-grade astrocytomas of the central nervous system is grim and has not been substantially improved by conventional chemoradiotherapy. We performed a multi-institutional phase I study to determine the toxicities and tolerance of concurrent external beam radiation of the brain and a unique dose-schedule of paclitaxel as a radiation sensitizer. PROCEDURE: Paclitaxel was delivered intravenously as a continuous 24 h/day, 7 days/week infusion during the entire 6-week course of fixed schedule standard radiation therapy. The dose of paclitaxel was escalated in patient cohorts in standard phase I design. RESULTS: Eleven patients (eight brain stem gliomas, one glioblastoma multiforme, and two gliomatosis cerebri) were treated. Dose-limiting toxicity was encountered in the two patients treated at 6 mg/(m(2)/24 h), both of whom developed severe obstipation requiring prolonged hospitalization. CONCLUSIONS: We have shown in this first study of its kind that paclitaxel can be administered safely to children as a 6-week continuous infusion concurrent with cranial irradiation. The maximally tolerated and recommended phase II dose is 4 mg/(m(2)/day). The benefits of taxanes as clinical radiation sensitizers for children with high-grade gliomas, if any, remain to be determined.

Adolescent↗
PubMed2001

Exploring the mechanisms of action of FB642 at the cellular level.

FB642(methyl-2-benzimidazolecarbamate, carbendazim) is a systemic fungicide belonging to the benzimidazole family with antitumor activity against a broad spectrum of tumors both in vitro and in vivo such as pancreas, prostate, colon, and breast. Although the preclinical antitumor activity of FB642 has been well explored, its mechanism of action has not been as well delineated. Previous studies indicate that FB642 may interfere with mitosis and thus may disrupt or inhibit microtubule function resulting in apoptosis. This study seeks to determine if FB642 is a sufficiently novel agent worthy of further development by examining the effect of FB642 on apoptosis, the cell cycle, p53-positive and -negative tumors, and drug-resistant and MDR cell lines. The results of this present study indicate that FB642 increases the degree of apoptosis in all examined tumor cell lines, may induce G2/M uncoupling, may selectively kill p53 abnormal cells, and exhibits antitumor activity in drug- and multidrug-resistant cell lines. The induction of apoptosis by FB642, particularly in p53-deficient cells, its impressive in vivo activity against a broad spectrum of murine and human tumors, as well as an acceptable toxicity profile in animals, make FB642 an excellent candidate for further evaluation in clinical trials in cancer patients.

Animals↗
PubMed2001

A phase I study of irinotecan in pediatric patients: a pediatric oncology group study.

A Phase I trial of irinotecan was performed to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the incidence and severity of other toxicities in children with refractory solid tumors. Thirty-five children received 146 courses of irinotecan administered as a 60-min i.v. infusion, daily for 5 days, every 21 days, after premedication with dexamethasone and ondansetron. Doses ranged from 30 mg/m2 to 65 mg/m2. An MTD was defined in heavily pretreated and less-heavily pretreated (i.e., two prior chemotherapy regimens, no prior bone marrow transplantation, and no radiation to the spine, skull, ribs, or pelvic bones) patients. Myelosuppression was the primary DLT in heavily pretreated patients, and diarrhea was the DLT in less-heavily pretreated patients. The MTD in the heavily pretreated patient group was 39 mg/m2, and the MTD in the less-heavily pretreated patients was 50 mg/m2. Non-dose-limiting diarrhea that was well controlled and of brief duration was observed in approximately 75% of patients. A partial response was observed in one patient with neuroblastoma, and in one patient with hepatocellular carcinoma. Stable disease (4-20 cycles) was observed in seven patients with a variety of malignancies including neuroblastoma, pineoblastoma, glioblastoma, brainstem glioma, osteosarcoma, hepatoblastoma, and a central nervous system rhabdoid tumor. In conclusion, the recommended Phase II dose of irinotecan administered as a 60-min i.v. infusion daily for 5 days, every 21 days, is 39 mg/m2 in heavily treated and 50 mg/m2 in less-heavily treated children with solid tumors.

Adolescent↗
PubMed2001

Squalamine treatment of human tumors in nu/nu mice enhances platinum-based chemotherapies.

Squalamine, an antiangiogenic aminosterol, is presently undergoing Phase II clinical trials in cancer patients. To broaden our understanding of the clinical potential for squalamine, this agent was evaluated in nu/nu mouse xenograft models using the chemoresistant MV-522 human non-small cell lung carcinoma and the SD human neuroblastoma lines. Squalamine was studied alone and in combination with either cisplatin or paclitaxel plus carboplatin. Squalamine alone produced a modest MV-522 tumor growth inhibition (TGI) and yielded a TGI with cisplatin that was better than cisplatin alone. Squalamine also significantly enhanced the activity of paclitaxel/carboplatin combination therapy in the MV-522 tumor model. Squalamine similarly improved the effectiveness of cisplatin in producing TGI when screened against the SD human neuroblastoma xenograft. Xenograft tumor shrinkage was seen for the MV-522 tumor in combination treatments including squalamine, whereas no tumor shrinkage was seen when squalamine was omitted from the treatment regimen. To gain a greater understanding of the mechanism by which squalamine inhibited tumor growth in the xenograft studies, in vitro experiments were carried out with vascular endothelial growth factor-stimulated human umbilical vein endothelial cells in culture exposed to squalamine. Squalamine treatment was found to retard two cellular events necessary for angiogenesis, inducing disorganization of F-actin stress fibers and causing a concomitant reduction of detectable cell the surface molecular endothelial cadherin (VE-cadherin). We propose that the augmentation by squalamine of cytotoxicity from platinum-based therapies is attributable to interference by squalamine with the ability of stimuli to promote endothelial cell movement and cell-cell communication necessary for growth of new blood vessels in xenografts after chemotherapeutic injury to the tumor.

Actins↗
PubMed2001

Elevated expression of DNA ligase I in human cancers.

PURPOSE: Human DNA ligase I plays an essential role in DNA replication, recombination, and repair by catalyzing the formation of phosphodiester bonds between adjacent 5'-phosphoryl and 3'-hydroxyl termini at single breaks in duplex DNA molecules. DNA ligase I is responsible for the majority of DNA ligase activity present in proliferating cells among four different forms of DNA ligases, designated DNA ligase I, II, III, and IV. In this study, we were interested in comparing DNA ligase I level in human tumors versus normal tissues and in studying whether the inhibition of DNA ligase I could lead to tumor cell death. EXPERIMENTAL DESIGN: DNA ligase I level was measured by Western immunoblot assay in various human malignant tumor specimens and benign tissues obtained from patients, in peripheral blood lymphocytes obtained from healthy donors, and in human tumors grown in nude mice. We also have designed antisense oligonucleotides (ODNs) targeting the mRNA of DNA ligase I and tested whether DNA ligase I antisense ODNs could control tumor cell growth. RESULTS: The amount of DNA ligase I enzyme in malignant tumors was considerably higher than that in benign normal tissues and peripheral blood lymphocytes. The level of DNA ligase I in human tumors grown in nude mice was also very high, and the expression of DNA ligase I appears to be constitutive during in vivo tumor development. We have observed that DNA ligase I antisense ODN inhibited tumor cell growth in a dose-response manner, but nonspecific control ODNs had little effect on the growth of the same cell lines. CONCLUSIONS: The presence of DNA ligase I at higher levels in human tumors than in benign normal tissues and normal peripheral lymphocytes suggests DNA ligase I plays more of a role in proliferating cells than in resting cells. These results, together with our finding that DNA ligase I antisense ODNs can suppress tumor cell proliferation, warrant the design and testing of human DNA ligase I inhibitors as new anticancer agents.

Animals↗
PubMed2000

Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.

PURPOSE: To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. PATIENTS AND METHODS: In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. RESULTS: Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. CONCLUSION: Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.

Adult↗
PubMed2000

Enhanced antitumour activity of 6-hydroxymethylacylfulvene in combination with topotecan or paclitaxel in the MV522 lung carcinoma xenograft model.

6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the toxin illudin S, which is a product of the Omphalotus mushroom. MGI 114 induces cytotoxicity against a broad range of solid tumours in vivo, including the drug-refractory MV522 human lung cancer xenograft. In this study, the potential application of MGI 114 in the treatment of lung cancer was explored by evaluating the activity of MGI 114 in combination with either topotecan (TPT) or paclitaxel. Groups of eight nude mice bearing MV522 xenografts were treated with MGI 114, TPT or paclitaxel as single agents and with MGI 114 in combination with TPT or paclitaxel. MGI 114 was administered at doses of 2.5 and 5.0 mg/kg intraperitoneally (i.p.) daily on days 1-5, while TPT and paclitaxel were administered at doses of 0.5 or 1.0 mg/kg and 20 mg/kg, respectively, i.p. on days 1-5. In the single-agent studies, MGI 114, TPT and paclitaxel all resulted in decreased final tumour weights compared with vehicle-treated controls. As single agents, TPT, at the 0.5 mg/kg dose level, and paclitaxel, at the 20 mg/kg dose level, produced partial shrinkages (PSs). All combinations of MGI 114, and either TPT or paclitaxel, produced decrements in final tumour weights compared with monotherapy with the same doses of MGI 114, TPT and paclitaxel. Although all animals treated with the combination of MGI 114 and paclitaxel experienced PSs or complete shrinkages (CSs) (or died), analysis of the time to tumour doubling revealed that the combination of MGI 114 and TPT at 2.5 and 0.5 mg/kg, respectively, was synergistic. These results suggest that cytotoxic activity is enhanced when MGI 114 is combined with either TPT or paclitaxel, and clinical trials to further evaluate these combination regimens are warranted.

Animals↗
PubMed2000

The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has activity against pancreatic human tumor xenografts.

There is a great need for new therapeutic agents for patients with advanced pancreatic cancer. The new dioxolane analogue troxacitabine was evaluated in two human pancreatic cancer xenograft models. The models used included the Panc-01 and MiaPaCa pancreatic cancer cell lines. Whereas there is certainly no absolute evidence that either of the in vivo models is predictive for clinical activity, there is at least some evidence that they may be helpful in selecting agents for clinical trials in patients with pancreatic cancer. Troxacitabine was administered i.v. to the animals at doses of 10 and 25 mg/kg on a daily x 5 regimen. Gemcitabine was used as a positive control. The end points for the study included tumor growth inhibition (TGI), final weight, and the number of partial and complete tumor responses in the animals. Troxacitabine was highly active against the Panc-01 model (n = 8), with TGI levels of 88.5% and 84.3% at the 10 and 25 mg/kg doses, respectively. The mean final tumor weights for animals given troxacitabine were also significantly smaller (P < 0.001) compared with vehicle controls. At the 10 mg/kg dose, there were three partial tumor shrinkages and one complete tumor shrinkage, whereas at the 25 mg/kg dose, there were three partial tumor shrinkages. Troxacitabine had less activity against the MiaPaCa model (n = 10) and, by traditional response criteria, would be considered inactive, with TGIs of 4% and 22.7% at the 10 and 25 mg/kg dose level, respectively. Of note is that in comparison with gemcitabine, troxacitabine was more efficacious against Panc-01 and was equally active against MiaPaCa. These in vivo results are encouraging and support the prospect of performing Phase II and perhaps Phase III trials with troxacitabine in patients with advanced pancreatic cancer.

Animals↗
PubMed2000

Development of SU5416, a selective small molecule inhibitor of VEGF receptor tyrosine kinase activity, as an anti-angiogenesis agent.

Angiogenesis, or the sprouting of new blood vessels, is a central process in the growth of solid tumors. For many cancers, the extent of vascularization of a tumor is a negative prognostic indicator signifying aggressive disease and increased potential for metastasis. Recent efforts to understand the molecular basis of tumor-associated angiogenesis have identified several potential therapeutic targets, including the receptor tyrosine kinases for the angiogenic factor vascular endothelial growth factor (VEGF). Here we review the approach taken at SUGEN, Inc. to discover and develop small molecule inhibitors of receptor tyrosine kinases as anti-angiogenic agents. We focus on SU5416, a selective inhibitor of VEGF receptors that is currently in clinical development for the treatment of advanced malignancies. Its biochemical, biological and pharmacological properties are reviewed and clinical implications discussed.

Angiogenesis Inhibitors↗
PubMed1999

Water soluble 20(S)-glycinate esters of 10,11-methylenedioxycamptothecins are highly active against human breast cancer xenografts.

Water-soluble 20(S)-glycinate esters of two highly potent 10,11-methylenedioxy analogues of camptothecin (CPT) have been synthesized and evaluated for their ability to eradicate human breast cancer tumor xenografts. The glycinate ester moiety increases the water solubility of the 10,11-methylenedioxy analogues 4-16-fold. However, in contrast to CPT-11, a water-soluble CPT analogue that was recently approved for second line treatment of colorectal cancer, the 20(S)-glycinate esters do not require carboxylesterase for conversion to their active forms. The glycinate esters are hydrolyzed to their parent, free 20(S)-hydroxyl active analogues in phosphate buffer (pH 7.5) and in mouse and human plasma. The glycinate esters are also 20-40-fold less potent than CPT-11 in inhibiting human acetylcholinesterase. In vivo, we examined 20(S)-glycinate-10,11-methylenedioxycamptothecin, 20(S)-glycinate-7-chloromethyl-10,11-methylenedioxycamptothecin, and CPT-11. We found that the two 10,11-methylenedioxy analogues had antitumor activity against breast cancer xenografts that was comparable to that of CPT-11. Our results indicate that water-soluble 20(S)-glycinate esters of highly potent CPT analogues provide compounds that maintain biological activity, do not require interactions with carboxylesterases, and do not inhibit human acetylcholinesterase.

Animals↗
PubMed1999

Enhanced antitumor activity of 6-hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model.

6-Hydroxymethylacylfulvene (MGI-114) is a semisynthetic analogue of the toxin illudin S, a product of the Omphalotus mushroom. MGI-114 induces cytotoxicity in a variety of solid tumors in vivo, including the refractory HT29 human colon cancer xenograft. In this study, the potential application of MGI-114 in the treatment of colon cancer was further explored by evaluating the activity of MGI-114 in combination with irinotecan (CPT-11) and 5-fluorouracil (5FU). Groups of 9 nude mice bearing HT29 xenografts were treated with either single agent MGI-114, CPT-11, or 5FU, or MGI-114 in combination with CPT-11 or 5FU. MGI-114 was administered at doses of 3.5 and 7 mg/kg i.p. daily on days 1 through 5, and CPT-11 and 5FU were administered at doses of 50 and 100 mg/kg i.p. on days 1, 12, and 19. In the single agent studies, MGI-114, CPT-11, and 5FU all resulted in decreased final tumor weights compared with vehicle-treated controls (P<0.05), but only MGI-114 at 7 mg/kg produced partial responses. When MGI-114 at 3.5 mg/kg was combined with CPT-11, significant decrements in final tumor weights occurred compared with monotherapy with the same doses of MGI-114 and CPT-11 (P< or =0.001). Also, administration of the low-dose combination (MGI-114 at 35 mg/kg and CPT-11 at 50 mg/kg) resulted in final tumor weights similar to those achieved after administration of high-dose MGI-114 as a single agent. Moreover, the combination of MGI-114 and CPT-11 produced partial responses in nearly all of the animals, with some animals achieving complete responses. The outcome with the combination of MGI-114 and 5FU was less striking, with fewer partial responses and no complete responses. These results suggest enhanced activity when MGI-114 is combined with CPT-11, and clinical trials to further evaluate this combination regimen are planned.

Animals↗
PubMed1999

Evidence of enhanced in vivo activity using tirapazamine with paclitaxel and paraplatin regimens against the MV-522 human lung cancer xenograft.

PURPOSE: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model. METHODS: Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration. RESULTS: Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine-paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not include tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens. CONCLUSIONS: These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted.

Animals↗
PubMed1999

Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay.

PURPOSE: This study was performed to evaluate the activity of the multitargeted antifolate (MTA or LY231514) against a broad range of human tumors taken directly from patients. MATERIALS AND METHODS: Human tumor colony-forming units were treated with MTA at concentrations of 0.1, 1.0, and 10 microg/ml in 1-h exposure studies. The responses of a limited number of specimens were also evaluated concurrently in 1-h exposures to cisplatin, fluorouracil, irinotecan, and/or paclitaxel. RESULTS: Of 358 specimens plated in the 1-h exposure studies, 148 (41%) were evaluable. Overall, responses were observed in 3% of specimens (4/144) at 0.1 microg/ml, 11% (17/148) at 1.0 microg/ml, and 23% (33/141) at 10 microg/ml. In this range of concentrations achievable clinically, there was a significant concentration-response relationship. At 10 microg/ml in the 1-h exposure studies, the response rate in colorectal cancer specimens was 32% (9/28), and the response rate in non-small-cell lung cancer was 25% (6/24). Responses were also observed in several chemoresistant tumors, including renal cell carcinoma, hepatocellular carcinoma, mesothelioma, and pancreatic carcinoma. The activity of MTA was not completely cross-resistant with that of cisplatin, fluorouracil, irinotecan, and paclitaxel. CONCLUSIONS: MTA demonstrated in vitro activity against a spectrum of tumors, including several tumors generally considered chemoresistant.

Antineoplastic Agents↗
PubMed1999

Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units.

BACKGROUND: The ras gene product regulates transduction of growth-proliferative signals from the membrane to the nucleus. Mutationally-activated Ras is the oncogene most frequently found in human tumors. In order to perform its function in cell signaling, Ras must be farnesylated on the CAAX motif present on the carboxyl terminus of the ras protein. This reaction is catalysed by farnesyl protein transferase. In the present study, SCH 66336, an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, was tested against a large variety of human tumors to define its preclinical activity profile, utilizing the human tumor cloning assay. MATERIALS AND METHODS: A soft agar cloning assay was used to determine the in vitro effects of SCH 66336 against primary human tumor specimens taken directly from patients. A total of 70 evaluable specimens were exposed to SCH 66336 for 14-day continuous exposure at concentrations ranging from 0.1 to 2.5 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. RESULTS: There was a positive relationship between concentration and response to SCH 66336. With the highest concentration (2.5 microM), response was demonstrated in 50% (three of six) of breast tumors, 40% (6 of 15) of ovarian tumors, and 38% (5 of 13) of non-small-cell lung tumor colony forming units. Among the 69 specimens tested at the concentration of 2.5 microM, SCH 66336 had activity in 27% of tumor specimens that were resistant to doxorubicin, 38% of tumor specimens resistant to cisplatin, 33% of tumor specimens resistant to paclitaxel, and 27% of tumor specimens resistant to etoposide. CONCLUSIONS: The broad spectrum of soft agar growth inhibition by SCH 66336 in the human tumor cloning assay, and its efficacy at physiologically relevant concentrations in animal models, suggest that SCH 66336 may deserve future clinical trials in patients with ovarian, breast and non-small-cell lung cancer.

Alkyl and Aryl Transferases↗
PubMed1999

A Phase I trial of bryostatin-1 in children with refractory solid tumors: a Pediatric Oncology Group study.

Bryostatin-1, a macrocyclic lactone, appears to elicit a wide range of biological responses including modulation of protein kinase C (PKC). PKC, one of the major elements in the signal transduction pathway, is involved in the regulation of cell growth, differentiation, gene expression, and tumor promotion. Because of the potential for a unique mechanism of interaction with tumorgenesis, a Phase I trial of bryostatin-1 was performed in children with solid tumors to: (a) establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); (b) establish the pharmacokinetic profile in children; and (c) document any evidence of antitumor activity. A 1-h infusion of bryostatin-1 in a PET formulation (60% polyethylene glycol 400, 30% ethanol, and 10% Tween 80) was administered weekly for 3 weeks to 22 children (age range, 2-21 years) with malignant solid tumors refractory to conventional therapy. Doses ranged from 20 to 57 microg/m2/ dose. Pharmacokinetics were performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. Twenty-two patients on five dose levels were evaluable for toxicities. At the 57 microg/m2/dose level dose-limiting myalgia (grade 3) was observed in three patients; two of those patients also experienced photophobia or eye pain, and one experienced headache. Symptoms occurred in all patients within 24-72 h after the second dose of bryostatin-1 with resolution within 1 week of onset. Other observed toxicities (grades 1 and 2) included elevation in liver transaminases, thrombocytopenia, fever, and flu-like symptoms. The bryostatin-1 infusion was typically well tolerated. Although stable disease was noted in several patients, no complete or partial responses were observed. The recommended Phase II dose of bryostatin-1 administered as a 1-h infusion weekly for 3 of every 4 weeks to children with solid tumors is 44 microg/m2/dose. Myalgia, photophobia, or eye pain, as well as headache, were found to be dose limiting.

Adolescent↗
PubMed1996

Pediatric phase I drug tolerance: a review and comparison of recent adult and pediatric phase I trials.

PURPOSE: We evaluated the ratio of pediatric to adult maximum tolerated doses (MTDs) from 70 Phase I studies conducted between 1975 and 1995. The aim of this study was to determine whether previously observed differences in drug tolerance between adult and pediatric Phase I patients have persisted over the 20-year period of this analysis. PATIENTS AND METHODS: Phase I trials of pediatric and adult patients with solid tumors as the predominant diagnosis and sharing similar dosing regimens were evaluated. For consistent comparison between Phase I studies, the MTD was defined as the drug dose one level below that yielding dose-limiting toxicity in >30% of patients. The ratio of pediatric to adult MTDs was calculated and plotted chronologically by year of pediatric study closure. Statistical evaluation of MTD ratios included regression and correlation analysis. The extent of therapy before Phase I study entry was also examined. RESULTS: Ninety-three Phase I studies were reviewed. Twenty-one drugs (70 studies) met our criteria for paired review of MTDs and analysis of the variation of ratio with time. The pediatric to adult MTD ratios ranged from 0.4 to 2.8, with a median of 1.2. Regression analysis of the ratio of MTD versus date of pediatric study closure supports a linear relationship of decreasing ratio with time (p<0.01). Analysis of the regression line predicts MTD ratios of 2.02 and 0.76 for 1974 and 1995, respectively. Of patients included in this analysis, 37.1% and 68.6% of adult and pediatric patients, respectively, were considered to have been heavily pretreated before study entry. A significant (p<0.001) downward trend with time was observed in the proportion of adult patients entering Phase I studies who had received both radiation and chemotherapy. CONCLUSIONS: The results of this review continue to show an equal or greater drug tolerance in the pediatric population when compared with adult patients for most drugs studied during Phase I trials. However, there appears to be significant trend of decreasing differences in drug tolerance between pediatric and adult Phase I patients with time, as defined by the descent of the MTD ratio toward values <1.0. Mechanisms to explain greater drug tolerance in children and the observation of decreasing maximum tolerated dose ratios with time are discussed. Limited data suggest that changes in degree of therapy before Phase I study entry may be influencing the MTD ratio.

Adult↗