Myotonia in patients treated for cancer with didemnin B.
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Adenocarcinoma↗
Biomedical subjects
D M Shin
Publications and source records attributed to D M Shin.
Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non-small cell lung cancer.
The authors treated 32 patients with Stage IIIB or IV non-small cell lung cancer (NSCLC) with an outpatient regimen of edatrexate (10-ethyl-10-deaza-aminopterin) (10-EdAM) on days 1 and 8, cyclophosphamide on day 1, and cisplatin on day 1, repeated every 3 weeks with dose modification. The 22 men and 10 women (median age, 57 years of age) had no prior chemotherapy and a Zubrod performance status less than or equal to 2. A schedule with initial doses of 80 mg/m2, 800 mg/m2, and 80 mg/m2, respectively, yielded a 47% major response rate with two complete responses (95% confidence interval [CI], 25% to 70%), but it also yielded significant stomatitis and myelosuppression. A schedule with reduced starting doses (70 mg/m2, 700 mg/m2, and 70 mg/m2) was better tolerated, but dropped the major response rate to 27% with no complete responses (95% CI, 11% to 52%). Median survival time was 39 weeks for all 30 evaluable patients without a significant difference between the treatment groups (which were comparable in patient characteristics). Major response, however, was associated with longer survival time than minor response or no change (P = 0.024) or progressive disease (P = 0.001) (median survival times, 55, 39, and 27 weeks, respectively). When the doses delivered were compared, patients treated with the reduced dose schedule received less mean 10-EdAM per course (P = 0.01), although the doses of cyclophosphamide and cisplatin were comparable to the original dose schedule for the second course and thereafter. These results suggest that this three-drug regimen may have synergistic antitumor effects, with a steep dose-response relationship, particularly with 10-EdAM. With amelioration of the dose-limiting stomatitis of 10-EdAM, it seems possible to maximize the antitumor effects of this regimen.
Adult↗
Phase II clinical trial of 4'-O-tetrahydropyranyl-adriamycin (THP-adriamycin) in recurrent squamous cell carcinoma of the head and neck.
Fourteen patients previously treated with surgery, radiotherapy, and/or chemotherapy for primary squamous cell carcinoma of the head and neck were treated with 4'-O-tetrahydropyranyl-Adriamycin (THP-adriamycin) for locally or distantly recurrent disease. The starting dose was 60 mg/m2 by i.v. infusion, with courses repeated every 3 to 4 weeks. A total of 34 courses of treatment were delivered (median, 2; range, 1-6). All patients were evaluable for response and toxicity. There were no responses. Severe (grade 3 or 4) neutropenia occurred in 11 patients. Thrombocytopenia, anemia, and gastrointestinal toxicity were modest, and no hepatic, renal, or cardiac toxicity was observed. The lack of response in association with severe neutropenia and moderate other toxicities using this dose and schedule of THP-Adriamycin should be taken into consideration prior to the pursuit of further study of this compound in a similar patient population.
Adult↗
Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting.
Didemnin B (NSC 325,319), a cyclic depsipeptide isolated from a Caribbean tunicate, exhibits potent preclinical antitumor activity. In previous phase I studies, 3.47 mg/m2 was the maximally tolerated dose, with nausea and vomiting being the dose-limiting toxicity. The drug was given in a single bolus infusion over 30 min every 28 days. In the current study, 30 patients presenting with previously treated non-small-cell lung cancer (NSCLC) received 46 courses of the drug at doses ranging from 3.47 to 9.1 mg/m2. Neuromuscular toxicity was dose-limiting. Nausea and vomiting appeared to be correlated with dose levels and were ameliorated by a combination of antiemetics including dexamethasone. Other side effects included a mild rise in hepatic enzymes and an allergic reaction that was preventable by the addition of corticosteroids to the premedication regimen. In all, 2 minor responses were seen among 24 evaluable patients. Because neuromuscular toxicity is dose-limiting, we recommend that routine measurements of creatine kinase and aldolase, a careful neurologic evaluation, and electromyography and muscle biopsy (if indicated) be incorporated into phase II trials. The recommended dose for phase II studies using a single bolus schedule is 6.3 mg/m2, following the premedication of patients with antiemetics.
Adult↗
Changes in keratin expression during 7,12-dimethylbenz[a]anthracene-induced hamster cheek pouch carcinogenesis.
This study was undertaken to explore the expression of keratins in the hamster cheek pouch carcinogenesis model, using monospecific keratin antibodies and a technique that allows immunoblotting analysis of tissues embedded in paraffin. Changes in keratin expression were correlated with histopathological changes and with the expression of the enzyme gamma-glutamyl transpeptidase. The right cheek pouch of 20 male golden Syrian hamsters was treated with 0.5% 7,12-dimethylbenz[a]anthracene for 16 weeks. As previously described by other laboratories, this treatment resulted in hyperplastic and dysplastic lesions and benign and malignant tumors. The keratins assayed in this study were K14 (Mr 55,000), K1 (Mr 67,000), and K13 (Mr 47,000). The normal hamster cheek pouch epithelium expressed K14 in the basal layer and K13 in the suprabasal and differentiated layers, whereas K1 was not detected by either immunohistochemistry or immunoblotting. Concomitant with 7,12-dimethylbenz[a]anthracene-induced hyperplasia, there were some topographical alterations in the distribution of K14. In this case, K14 was no longer restricted to the basal layer but was also expressed in differentiated cells. The same pattern was also observed in dysplastic lesions and in squamous cell carcinoma. Furthermore, expression of the K13 differentiation-associated keratin was preserved in this hyperplastic epithelium during all the stages of carcinogenesis, including either anaplastic or differentiated areas. In contrast, after 2 weeks of 7,12-dimethylbenz[a]anthracene treatment, K1 expression started as a weak and patchy pattern in suprabasal cells, becoming stronger and more homogeneous at 8 and 16 weeks of treatment. However, K1 was almost absent in squamous cell carcinoma, where only small very well differentiated areas were stained. We also observed gamma-glutamyl transpeptidase-positive foci in earlier stages of carcinogenesis, concomitant with the expression of the K1 keratin. However, it was not possible to find a perfect topographical correspondence between the two events. Alterations in the pattern of keratin expression appear to be a common feature during the development of squamous cell carcinoma in different systems and could be an excellent tool to study carcinogenesis and chemoprevention.
9,10-Dimethyl-1,2-benzanthracene↗
Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model.
The expression of epidermal growth factor receptor and transglutaminase type I, polyamine (putrescine, spermidine, and spermine) levels, ornithine decarboxylase activity, and micronuclei occurrence were assessed in the 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch model to elucidate the role and timing of changes in different growth and differentiation markers during carcinogenesis. DMBA (0.5%) in heavy mineral oil was applied to the right buccal pouch 3 times per wk for up to 16 wk; controls received heavy mineral oil alone. Hamsters were killed after 0, 4, 8, and 16 wk. Frozen tissue was chemically analyzed for polyamine levels and ornithine decarboxylase activity and was also used for immunohistochemical analysis of transglutaminase I. Paraffin-embedded sections were used for epidermal growth factor receptor immunohistochemical determinations and for micronucleated cell assays. Hyperplasia was detected by histological analysis at 4 wk, dysplasia with or without papillomatous changes at 8 wk, and squamous cell carcinoma at 16 wk. Epidermal growth factor receptor was not expressed in the normal buccal epithelial layer, at a moderate level in both the superficial keratin and basal cell layers in hyperplastic epithelium, and at very high levels in both dysplasia and squamous cell carcinoma. Transglutaminase I was expressed at a limited level in normal buccal mucosa, was expressed at a low level in the basal layer of hyperplastic lesions, was somewhat elevated in dysplasia, and was markedly enhanced in squamous cell carcinoma. Putrescine and spermidine levels and ornithine decarboxylase activity increased dramatically after 8 and 16 wk of DMBA. Micronucleated cells increased after 4 wk of DMBA treatment, that high level sustained during all stages of carcinogenesis. We suggest that these biological markers could be excellent intermediate end points in assessing the effects of various chemopreventive agents to be tested in the hamster buccal pouch model and in human clinical trials.
9,10-Dimethyl-1,2-benzanthracene↗
Intrabronchial implantation of the Lewis lung tumor cell does not favor tumorigenicity and metastasis.
The purpose of these studies was to determine whether the orthotopic implantation of the Lewis lung tumor favors tumorigenicity and production of metastasis as compared with implantation at an ectopic site. Different numbers of viable cells were implanted subcutaneously (footpad), intrabronchially, or intrathoracically into groups of syngeneic mice. Tumorigenicity, production of distant metastases and survival were recorded. Tumor cells implanted subcutaneously produced fast-growing local tumors and numerous spontaneous lung metastases. Tumor cells implanted intrabronchially produced slow-growing tumors that did not produce distant metastasis. Since radiolabeled cells implanted into different sites exhibited similar patterns of survival, the differences in behavior of 3LL cells in the skin or lung were due to other factors. We conclude that for the Lewis lung carcinoma, orthotopic implantation does not favor increased tumorigenicity and metastatic potential.
Animals↗
Designing a culturally sensitive AIDS educational program for black and Hispanic women of childbearing age.
A disproportionate number of AIDS cases is seen among Hispanics and women. However, there is a lack of knowledge relative to effectively educating and motivating behavioral change among minority women at risk for HIV infection. Using the Health Belief Model as a framework to promote behavioral change, methods for designing a culturally sensitive AIDS educational program that appropriately addresses the needs of a population at risk, are given. A list of national resources relating to AIDS resources for the black and Hispanic community is also provided.
Acquired Immunodeficiency Syndrome↗
Superior antiproliferative effects mediated by interferon-alpha entrapped in liposomes against a newly established human lung cancer cell line.
The purpose of this study was to characterize the antiproliferative activity of a recombinant interferon-alpha (IFN-alpha) against a newly established human adenocarcinoma cell line (DMS-4C) and to determine whether IFN-alpha entrapped in multilamellar liposomes had superior antitumor effects compared with free IFN-alpha. Treatment of DMS-4C cells with 100 U/ml of free IFN-alpha resulted in 34% cytostasis. IFN-alpha encapsulated in phosphatidylcholine/phosphatidylserine multilamellar vesicles produced growth inhibition of 67%, which was significantly greater than that produced by free IFN-alpha or by control liposomes containing only medium combined with free IFN-alpha. Moreover, kinetic analysis revealed that to produce significant cytolysis, free IFN-alpha had to be incubated with target cells for at least 24 h, whereas IFN-alpha encapsulated into liposomes required only 30 min of exposure.
Adenocarcinoma↗
Reduction to homozygosity at the SIS/PDGF-2 locus in human mesenchymal tumors.
Enhanced expression of the human SIS/PDGF-2 gene has been reported in a number of human cell lines, sarcomas, and glioblastomas. We have analyzed the SIS/PDGF-2 gene for structural alterations in fresh human tumors. DNA samples from 79 patients with solid tumors (63 mesenchymal tumors, 12 lung carcinomas, 4 breast carcinomas) were examined and compared with DNA samples from 50 leukemia patients and 14 unrelated individuals without malignant neoplasms. When DNA samples were digested with a HindIII restriction endonuclease, Southern blot analysis demonstrated two distinct bands (21kb and 18kb) after hybridization to the SIS/PDGF-2 gene probe. A pedigree analysis of a 43-member family indicated that these allelic variants segregated in a Mendelian fashion. There was, however, tumor specific allele loss in 18% of the mesenchymal tumors analyzed, which may indicate a common etiology for this tumor type.
Cell Line↗
Phase I study of paclitaxel administered by ten-day continuous infusion.
PURPOSE: Pre-clinical data have suggested that prolonged exposure to paclitaxel enhances its cytotoxicity, but various clinical trials utilizing long-term infusions of paclitaxel have been limited by unacceptable hematologic toxicity, most notably significant neutropenia. A phase I study of paclitaxel administered over 10 days, was performed to evaluate the hematologic and non-hematologic toxicities as well as to determine the maximum-tolerated dose for the 10-day infusion duration. PATIENTS AND METHODS: Twenty-nine solid tumor patients (predominantly non-small cell lung cancer and head and neck cancer) were treated with paclitaxel at doses ranging from 5 mg/m2/day to 25 mg/m2/day administered as a 10-day continuous infusion via a pump every 21 days. Dose escalation was permitted within individual patients. Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic toxicity, ANC < or = 500 or platelet count < or = 25,000 for > or = 7 days or febrile neutropenia. The maximum tolerated dose (MTD) was defined as the highest dose level at which less than two out of six patients developed DLT. All of the patients had received prior chemotherapy; approximately two-thirds had received prior radiation as well. All patients received standard pre-medications for paclitaxel, including anti-histamines and corticosteroids. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used. RESULTS: A total of 110 courses of paclitaxel were administered to 29 patients. The incidence of hematologic and non-hematologic toxicity was quite low among the patients treated at dose levels below 17 mg/m2/day. At higher doses, non-hematologic toxicities including arthralgias, myalgias, fatigue, nausea, stomatitis, and peripheral neuropathy were seen, although nearly all of the toxicities were less than grade 3 (NCI toxicity criteria). Hematologic toxicity mostly consisted of neutropenia and was more common at dose levels of 17 mg/m2/day or higher. Nevertheless, even at the highest dose levels (21 mg/m2/day and 25 mg/m2/day) grade 3 or 4 neutropenia occurred in only 50% of patients. Dose-limiting hematologic toxicity occurred in 2 of 4 patients treated at the 25 mg/m2/day dose level. CONCLUSION: Paclitaxel can be safely administered as a 10-day infusion. The MTD for this schedule is 210 mg/m2. Unlike the 96-hour paclitaxel infusions, dose-reduction for myelosuppression may not be necessary because the MTD of paclitaxel when administered over a 10-day infusion is similar to the MTD of paclitaxel when infused over 3 or 24 hours.
Adult↗
Study of multidrug resistance (mdr1) gene in non-small-cell lung cancer.
Non-small-cell lung cancer (NSCLC) is one of the tumors that shows intrinsic drug resistance to various chemotherapeutic agents. We investigated a possible role of the multidrug resistance (mdr1) gene amplification using a DNA slot blot analysis in 23 untreated non-small-cell lung cancer tissues and 14 corresponding adjacent normal lung tissue samples. In all instances, whether tumors or adjacent normal tissue samples, DNA amplification was not detected except in 1 adenocarcinoma and 2 squamous cell carcinomas that had a low level of amplification of mdr1 gene. In addition, 6 untreated tumors and 7 normal tissue samples were examined for mdr1 RNA expression using RNA slot blot analysis. Only low levels of mdr1 expression were observed in all cases. We conclude that mechanisms other than mdr1 amplification or expression account for the intrisic drug resistance of non-small-cell lung cancers.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Simultaneous amplification of epidermal growth factor-receptor and multidrug-resistance genes in a newly. Established human lung cancer cell line.
We have investigated amplification and expression of the epidermal growth factor (EGF)-receptor gene and the multidrug-resistance (MDRI) gene in a newly established lung adenocarcinoma cell line and its subcell lines. Of these cell lines, the EGF-receptor was amplified (64-fold) and rearranged (6.5 and 5.4 Kb with EcoRI restriction) in an early passage cell line, DMS-4CS. MDRI gene amplification (10.5-fold), accompanied by rearrangement (4.6 and 3.7 Kb with Hind III restriction), was found in the same cell line. All other subcell lines derived from DMS-4C5 failed to demonstrate any amplification of these genes. Moreover, mRNA expression of these two genes was not overproduced. Our findings seem to indicate that highly selected cells at an early stage have undergone spontaneous amplification of these genes. However, cells containing such amplified DNA sequences may exhibit growth disadvantage, and, therefore, the amplified DNA sequences were not present in the sublines. The cytogenetic study demonstrated that early passage cells, DMS-4C6, only showed one unique marker chromosome, M10, which may represent amplification of these genes in question.
Adenocarcinoma↗
Aberrant oncogene expression in uncultured human sarcoma and melanoma.
Protooncogenes have the ability to induce and/or maintain the transformed state when they are overly expressed or altered by mutation or gene rearrangement. To study the possible involvement of these cellular oncogenes in the neoplastic transformation, we have analyzed their expression in 44 fresh samples obtained from primary, recurrent, or metastatic tumors from patients with a variety of sarcomas and a melanoma. Our analysis was carried out by the northern blot technique using poly (A)+ RNA hybridized with human cellular DNA probes. A normal 2.3-kb c-myc transcript was observed almost universally at various levels. A normal c-k-ras transcript of 5.2-kb was detected at a low level in most of the samples. In three samples we detected aberrant c-k-ras transcripts of 7.0 and 8.5-kb, while in two other samples we found an aberrant lower-molecular-weight transcript of 1.4-kb. N-myc was expressed in only three samples, and in all instances, the transcripts were aberrant (more than 10-kb). A normal 3.7-kb c-sis transcript was expressed at a low level in most of the sarcomas and the melanoma but was uniquely overexpressed in giant cell tumors of bone. C-fos (2.2-kb) was expressed at a low level in almost half of the samples; c-myb was never expressed. We conclude that c-k-ras, n-myc, c-sis, and c-myc are aberrantly or overexpressed in sarcoma/melanoma, and their activation may play a role in the transforming events leading to development and/or progression of these tumors.
Gene Expression Regulation↗