Biomedical subjects
S Weitman
Publications and source records attributed to S Weitman.
Pediatric phase II cancer chemotherapy trials: a Pediatric Oncology Group study.
PURPOSE: This study reviewed the Pediatric Oncology Group experience with phase II clinical trials in children (< 21 years of age) with refractory tumors. PATIENTS AND METHODS: Patients registered in Pediatric Oncology Group phase II studies were evaluated. Patients had to be < 21 years of age with recurrent and refractory measurable disease. Tumor types and response rates were determined. Death on therapy from either drug toxicity, progressive disease, infection, or hemorrhage was measured. Tumor-specific, disease-free survival curves were calculated by Kaplan-Meier analysis. RESULTS: Between 1984 and 1994, 2,465 patient entries were made on 45 phase II trials. Malignancies registered included acute lymphocytic leukemia (ALL) (16.7%), acute myeloid leukemia (AML) (12.0%), osteogenic sarcoma (7.8%), neuroblastoma (7.2%), astrocytoma (7.2%), medulloblastoma (7.1%), glioma (6.7%), ependymoma (6.1%), and others (29.2%). The overall response rate was 19.6% (CR + PR) for children entered on phase II trials. Tumor-specific response rates ranged from 62.1% (23/37) for children with Hodgkin's disease to no responses (0/23) in patients with hepatoblastoma. When comparing single versus multiagent trials, a significantly better initial response rate was seen in the latter studies. However, 5-year survival was comparable. Progression-free survival for all tumor histologies were 12.9% and 9.2% at 2 and 5 years, respectively. Death on study was seen in 11.6% of the patients; however, only three deaths were directly related to drug toxicity. There were no significant gender differences in regards to response, progressive disease, or death on study. CONCLUSION: Phase II studies conducted in children offer a considerable likelihood of therapeutic benefit without exposing these patients to untoward toxicity.
In vitro antitumor activity of rebeccamycin analog (NSC# 655649) against pediatric solid tumors.
PURPOSE: This study determined the in vitro antitumor activity of a rebeccamycin analog (NSC# 655649) using tetrazolium/formazan (MTT) and clonogenic assays against established pediatric cell lines and solid tumor specimens obtained from children. MATERIALS AND METHODS: Tumor cells from 14 established cell lines and 20 patient specimens were exposed in vitro for 1 hour to NSC# 655649 at concentrations ranging from 0.015 to 15.0 microM. The cytotoxicity (IC50) of this agent against established cell lines was determined using both the MTT (cytotoxic) and clonogenic/soft agar cloning (cytostatic) assays. Tumor specimens from children undergoing biopsy or surgical resection were also evaluated in vitro against NSC# 655649 using the clonogenic assay. For studies using patient specimens, antitumor activity was measured by comparing the number of tumor colonies from NSC# 655649-treated cells with those from solvent-treated controls. RESULTS: These studies showed that the mean IC50S using the MTT and clonogenic assays using established solid tumor cell lines were 0.94 and 0.51 microM, respectively. In general, for cell lines tested using both types of assays, the clonogenic assay resulted in a smaller IC50. The overall in vitro responses (< or = 50% survival compared to controls) using patient tumor specimens and the clonogenic assay were 35% (1.5 microM), 60% (7.5 microM), and 80% (15.0 microM). Of the 9 patients with neuroblastoma, responses to NSC# 655649 were seen in 33% (1.5 microM), 58% (7.5 microM), and 92% (15.0 microM) of the specimens. Prior chemotherapy did not appear to adversely affect in vitro responses. CONCLUSIONS: NSC# 655649 appears to have broad antitumor activity in vitro against pediatric malignancies at drug concentrations achieved during adult phase I clinical trials. These studies support the further development of NSC# 655649 for solid tumors in children.
Phase I therapy trials in children with cancer.
PURPOSE: This study examined the response and toxicity rates of antineoplastic drugs evaluated in phase I clinical trials in children to identify trends in response and toxicity over time. PATIENTS AND METHODS: Full length, peer-reviewed articles describing the results of single agent phase I therapy trials in children younger than 21 years with cancer were reviewed. Tumor-specific response data and doses of drugs that resulted in objective responses were noted. Deaths that occurred on study caused by drug toxicity, progressive disease (PD), or complications of marrow aplasia were identified, along with drug doses that resulted in toxic death. Temporal trends in response rates, toxicity, and number of patients entered in trials were examined. RESULTS: A total of 1,606 patients with cancer were enrolled in 56 single-agent pediatric phase I therapy trials published between 1978 and 1996. Of these, 1,257 were evaluated for response by tumor type. The overall objective response rate was 7.9%. Response rates were highest for patients with neuroblastoma (17.7%) and acute myelogenous leukemia (11.6%). Patients with osteosarcoma and rhabdomyosarcoma had response rates of < 3%. Sixty percent of responses in patients with solid tumors occurred at 81 to 100% of the maximum tolerated dose (MTD), although 42% of responses in patients with leukemia occurred at > 100% of the MTD. Death on study was noted in 7.0% of all patients entered in trials. Only 0.7% of patients experienced a death related to drug toxicity. PD accounted for the death of 5.6% of study participants. A trend of increasing response rate despite smaller trial size was noted over the last 7 years of this period. CONCLUSION: Phase I trials in children with cancer represent a safe mechanism to determine the MTD, toxicity profile, and pharmacokinetics of new agents for use in children with cancer.
MGI 114: augmentation of antitumor activity when combined with topotecan.
PURPOSE: 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the mushroom toxin illudin S that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound. The studies were conducted to evaluate the antitumor activity of MGI 114 as a single agent and in combination with topotecan against pediatric solid tumor cell lines and xenograft models. MATERIALS AND METHODS: In vitro studies were designed to determine the cytotoxic potential of MGI 114 using the MTT assay and 13 pediatric tumor cell lines. In addition, combination in vitro studies were performed with MGI 114 and topotecan to generate isoeffect plots. Single agent and combination in vivo studies were also performed using MGI 114 against rhabdomyosarcoma and neuroblastoma xenograft models. RESULTS: After a 1-hour exposure to MGI 114, the mean IC50 (+/-standard error of mean) for medulloblastoma, neuroblastoma, Ewing sarcoma/primitive neuroectodermal tumor, and rhabdomyosarcoma cell lines were 1.58+/-0.51, 1.60+/-0.82, 1.18+/-0.08, and 3.99+/-1.69 microg/mL, respectively. When tumor cells were exposed concurrently to MGI 114 and topotecan, evidence of synergy was observed in 10 of 12 (83%) cell lines. Single agent and combination in vivo studies with MGI 114 showed that this agent had substantial, and at times curative, antitumor activity against rhabdomyosarcoma and neuroblastoma xenograft tumors. CONCLUSIONS: These data suggest that MGI 114 has significant efficacy as a single agent in preclinical studies against pediatric tumors. In addition, based on previous reports and the results presented here, combining MGI 114 with topotecan appears to be an attractive approach to the treatment of pediatric malignancies. After completion of the pediatric phase I studies of MGI 114, consideration should be given to phase II single agent and phase I combination studies with a topoisomerase I inhibitor such as topotecan or irinotecan.
Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts.
The objective of this study was to investigate the cytotoxic activity of irofulven (HMAF, MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of ovarian cancer. Antiproliferative effects of irofulven in ovarian cancer cell lines and ovarian tumor specimens were characterized in vitro using sulforhodamine B and human tumor colony-forming assays, respectively. Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human tumor cloning assays, irofulven inhibited colony formation in surgically derived ovarian tumors at concentrations as low as 0.001 micro g /ml and indicated superior activity in comparison with paclitaxel when tested against the same tumor specimens. The antitumor activity of irofulven compared to that of paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3 tumors, treatment with paclitaxel failed to inhibit tumor growth; whereas mice treated with maximum tolerated doses of irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean tumor growth inhibition of 82%. The potent activity of irofulven against ovarian tumors in vitro and in vivo supports the evaluation of its clinical activity in ovarian cancer.