The correlation between peripheral neuropathy and cisplatin (CDDP) was elucidated in 27 patients with primary and metastatic lung cancer, who were treated with Adriamycin 30 mg/m2 day 1, CDDP 80 mg/m2 day 1, and VP-16 70 mg/m2 day 1-5 every 4 weeks. The incidence of peripheral neuropathy was 33% (9 of 27 patients) and it increased to 60% in the patients who received over 320 mg/m2 of CDDP, demonstrating a positive correlation between the incidence of this toxicity and the total dose of CDDP. However, no significant relation was observed between the grade of neuropathy and CDDP. The neuropathy was manifested in the sensory system of the distal extremities and was developed into proximal portions. The peripheral neuropathy with grade 3 was irreversible, resulting in the dose-limiting factor of this regimen.
Point mutations of the RET proto-oncogene are associated with the development of inherited diseases including multiple endocrine neoplasia (MEN) type 2, familial medullary thyroid carcinoma (MTC), and Hirschsprung's disease as well as a part of sporadic MTCs and pheochromocytomas. In the present study, we examined point mutations of the RET proto-oncogene in exons 10, 11 and 16 in small cell lung carcinoma (SCLC) cell lines. A novel point mutation from GCC to GAC at colon 664 in exon 11 was identified in 2 out of 6 SCLC cell lines; this alteration results in an amino acid substitution of aspartic acid for alanine. This point mutation was not detected in other types of cancer cell lines so far examined. Point mutations of the RET proto-oncogene reported previously inexons 10, 11 and 16 in above-mentioned diseases were not detected in the SCLC cell lines. These results suggest that this point mutation of the RET proto-oncogene is closely associated with a part of SCLC.
We examined whether lymphatic metastasis was inhibited by the potent angiogenesis inhibitor AGM-1470 [O-(chloroacetyl-carbamoyl)fumagillol, TNP-470] using a rat lymphatic metastasis model. Clone A of the rat fibrosarcoma AS653HM, when inoculated into the footpads of syngeneic rats, highly and preferentially metastasized to lymph nodes. In contrast, when AGM-1470 was administered subcutaneously to rats bearing the tumor cells, the tumor growth and incidence of metastasis in the lymph nodes were reduced in a dose- and schedule-dependent manner. Similar inhibition of lymphatic metastasis was also observed in the rats in which treatment with AGM-1470 was initiated following resection of the primary tumor in the foot, indicating that the treatment with AGM-1470 inhibited the progression of lymphatic metastasis at the metastatic sites of the lymph nodes. These results suggest that AGM-1470 can be a potential agent to prevent lymphatic metastasis.
Through our retrospective analysis of HTCA and clinical effects as well as fundamental studies, the following results were obtained: In this retrospective study, HTCA for lung cancer showed a predictive accuracy of 71%, a true positive rate of 50% and a true negative rate of 77%. To obtain good predictive accuracy, HTCA should be modified to provide conditions comparable to those in vivo with regard to drug concentration and drug exposure time. More precise analysis of the pharmacokinetics of anticancer agents might yield methodological improvement. A decrease in the chemosensitivity spectrum in vitro was observed after chemotherapy. This might be related to evidence that patients with prior chemotherapy exhibited a poor response rate to chemotherapy. There were no active anticancer agents against specimens with aplating efficiency of more than 0.04%. More extensive prospective trials will be necessary to determine the clinical value of HTCA. HTCA could be a superior assay for detecting the anti-tumor activity of new agents and a useful method for in vitro phase II study.
Abstract Neuroblastoma is the most common extracranial solid tumors in children and high-risk patients with such tumors have a poor prognosis despite recent advances with multimodal therapies. Retinoic acids have been clinically used for some cancers including neuroblastoma although the mechanism of their antitumor effect remains to be fully elucidated. It was recently reported that gene amplification and gain-of-function mutation of ALK were found in tumors from some neuroblastoma patients; and RNAi or small molecule inhibitors of ALK induced apoptotic cell death in neuroblastoma cell lines with these genetic alterations of ALK. In this study, we found that all-trans retinoic acid (ATRA) downregulated ALK expression in neuroblastoma cell lines; and the suppression of ALK by ATRA accompanied apoptotic cell death in neuroblastoma cell lines with activated ALK. We used four neuroblastoma cell lines: NB-39-nu cells with gene amplification of ALK, SH-SY5Y cells with gain-of-function mutation of ALK as well as TNB-1 and GOTO cells without such genetic alterations. Western blotting analysis demonstrated that the levels of ALK protein were remarkably reduced in all cell lines treated with ATRA at the concentration of 1 μM or 10 μM for 72 h. Analysis by quantitative real-time RT-PCR for mRNA expression levels in ATRA-treated NB-39-nu cells revealed that the ALK mRNA quantitative levels of the cells reduced at 24 h after such treatment. Apoptosis assays demonstrated obvious apoptosis in NB-39-nu and SH-SY5Y cells whereas it was not evident in TNB-1 and GOTO cells. Cleaved caspase-3 was also detected in NB-39-nu and SH-SY5Y cells 72 h after treatment with ATRA, but not in TNB-1 and GOTO cells. In addition, we observed cell growth inhibition that was accompanied with apoptosis in NB-39-nu and SH-SY5Y cells treated with ATRA. These results suggest that ALK downregulation by ATRA might lead to apoptotic cell death in neuroblastoma cells with activated ALK. This finding further suggests that ALK downregulation by retinoic acids could contribute to their therapeutic effect in a subset of neuroblastoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-3.
In this study, recombinant human IL-1 alpha (rhIL-1 alpha) was used to protect normal and tumor-bearing BALB/c mice from the acute toxicity caused by lethal doses of cyclophosphamide (Cy) and 5-fluorouracil. Pretreatment of mice for 7 days with 10,000 U/day of rhIL-1 alpha protected 70 to 100% of mice from the acute death induced by lethal doses of both Cy (380 mg/kg) and 5-fluorouracil (250 mg/kg). In contrast, post-treatment of mice with single or multiple doses of rhIL-1 alpha was not chemoprotective. Pretreatment of mice with rhIL-1 alpha increased the acute LD90 of Cy from 380 mg/kg to greater than 500 mg/kg in normal mice, an LD90 dose-modifying effect of at least 1.25, was accompanied by a more rapid recovery from neutropenia and a less severe reduction in the number of bone marrow single lineage monocyte, myeloid, or myelomonocytic colonies. Some of the mice (10 to 50%) that were successfully protected by pretreatment with rhIL-1 alpha died after day 50. These mice consistently presented with extensive pulmonary inflammation and fibrosis at death. Mice bearing murine renal cancer (Renca) were also protected from the acute toxic effects of Cy (450 mg/kg) by pretreatment with rhIL-1 alpha. Renca-bearing mice pretreated with rhIL-1 alpha and either sublethal (300 mg/kg) or lethal (450 mg/kg) doses of Cy exhibited enhanced survival times over those of untreated Renca-bearing mice. Interestingly, the cause of death in Renca-bearing mice that ultimately failed treatment with rhIL-1 alpha plus 300 mg/kg Cy was recurrent tumor, whereas most mice treated with rhIL-1 alpha plus 450 mg/kg Cy had no detectable tumor, although several died from late pulmonary inflammation and fibrosis. Thus, the dose escalation of Cy in rhIL-1 alpha-pretreated mice results in greater antitumor effects of Cy. However, the dose escalation of some cytotoxic agents allowed by the use of myelostimulatory agents can result in late fatal complications not detected in acute toxicity testing.
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