Biomedical subjects

B Teicher

Publications and source records attributed to B Teicher.

11 recordsLinked to original sources

PubMed2000

Double high-dose chemotherapy with stem cell rescue (HD-SCR) in patients with breast cancer - effect of sequence.

INTRODUCTION: A preliminary analysis of our double high-dose chemotherapy with stem cell rescue (HD-SCR) clinical trial for breast cancer, and preclinical cross-resistant studies, suggested that melphalan (M) adversely affected response to subsequent chemotherapy, i.e., that the sequence of alkylating agents (AAs) might affect response. We, therefore, constructed and examined preclinical models to determine whether prior exposure to M, in fact, adversely affected response to other therapy. PURPOSE: The purpose of the study was to determine whether the sequence of AAs, specifically the prior use of M, adversely affected response to subsequent treatment. METHODS: The methods employed were the following: (1) Human tumor cell lines rendered resistant by in vitro sequential exposure to five different AAs were developed. The resistant cell lines were examined for cross-resistance to alkylating and other agents. (2) In vivo studies in the p388 mouse leukemia for resistance and cross-resistance among the AAs. (3) In vivo studies of the effect of sequence of AAs on response in mice bearing EMT6 breast cancer. (4) The double transplant model was developed in the mouse and the sequence of high-dose AAs was studied. (5) Biochemical and reverse transcriptase-polymerase chain reaction (RT-PCR) studies of the various resistant tumor cell lines. RESULTS: (1) The in vitro human tumor cells resistant to M were cross-resistant in 57% of tests to other AAs. In contrast, resistance for other AAs crossed to other agents in only 10 to 20% of tests. (2) The in vivo studies of p388 indicated that resistance to M commonly crossed to other AAs and many non-AAs. (3) The results for the mouse breast cancer (EMT6) studies of the sequence of AAs again indicated that M employed first markedly reduced responsiveness to subsequent treatment, particularly with AAs. (4) The double transplant model: again, M first markedly reduced response to other agents. (5) The in vitro resistant human tumor cell lines, particularly the breast cancer cell line MCF7, were found to contain high concentrations of glutathione S1 transferase gamma, which is consistent with that mechanism being responsible for resistance. CONCLUSION: The sequence of alkylating agent treatment may substantially influence response. Melphalan, particularly, produces resistance that commonly crosses to the other AAs. Mechanistic studies indicate significant changes in glutathione S1 transferase, a known mechanism for broadly based resistance to AAs.

Alkylating Agents↗

PubMed1998

Abrogation of mitochondrial cytochrome c release and caspase-3 activation in acquired multidrug resistance.

Acquired multidrug resistance to anti-cancer agents has been associated with overexpression of the P-glycoprotein and other members of the ATP-binding cassette superfamily. The present studies demonstrate that SCC-25 cells selected for resistance to the alkylating agent cisplatin (CDDP) overexpress the anti-apoptotic Bcl-xL protein. In contrast to parental cells, the SCC-25/CDDP-resistant variant failed to exhibit activation of caspase-3, cleavage of protein kinase C delta, and other characteristics of apoptosis in response to CDDP. Similar results were obtained when SCC-25/CDDP cells were exposed to the structurally and functionally unrelated antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C). Other cells selected for resistance to doxorubicin or vincristine also exhibited overexpression of Bcl-xL and failed to respond to CDDP and ara-C with activation of caspase-3. The results further demonstrate that multidrug-resistant cells exhibit a block in the release of mitochondrial cytochrome c into the cytosol and that this effect is dependent on overexpression of Bcl-xL. The demonstration that lysates from the resistant cells respond to the addition of cytochrome c with activation of caspase-3 confirms that the block in apoptosis is because of inhibition of mitochondrial cytochrome c release. These findings demonstrate that cells respond to diverse classes of anti-cancer drugs with overexpression of Bcl-xL and that this response represents another mechanism of acquired multidrug resistance.

Antineoplastic Agents↗

PubMed1998

Jasplakinolide: interaction with radiation and hyperthermia in human prostate carcinoma and Lewis lung carcinoma.

PURPOSE: Jasplakinolide is a novel natural product anticancer agent which acts by inducing overpolymerization of actin. The aim of the current study was to explore the activity of jasplakinolide with hyperthermia and radiation. METHODS: The response of human PC-3 and DU-145 prostate carcinoma cells and DU-145 xenografts and the response of the Lewis lung carcinoma to jasplakinolide were studied. RESULTS: Jasplakinolide was cytotoxic toward human prostate carcinoma cells, DU-145, PC-3 and LNCaP in culture, killing 1 log of cells with 0.8, 0.3 and 0.07 microM of drug in 24 h, respectively. The combination of jasplakinolide and hyperthermia resulted in primarily additive cell killing by the two modalities in the three prostate carcinoma lines. In combination with radiation, jasplakinolide produced some diminution in the shoulder of the survival curve of normally oxygenated PC-3 cells and was a radiation sensitizer of hypoxic DU-145 cells and hypoxic PC-3 cells. In vivo, jasplakinolide was an active antitumor agent against the Lewis lung carcinoma and the DU-145 prostate carcinoma xenograft. Jasplakinolide was a radiation sensitizer in the Lewis lung carcinoma. Jasplakinolide was also effective against the systemic Lewis lung carcinoma, decreasing lung metastases. Lung metastases were further decreased when jasplakinolide was administered along with radiation to the subcutaneous primary tumor. In the DU-145 tumor, the effects of jasplakinolide and fractionated radiation for 1 or 2 weeks appeared to be primarily additive. CONCLUSION: Jasplakinolide is an interesting new anticancer agent for which further study both as an anticancer agent and in combined modality regimens is warranted.

Animals↗

PubMed1994

Phase I pharmacokinetic study of the hypoxic cell sensitizer etanidazole with carboplatin and cyclophosphamide in the treatment of advanced ovarian cancer.

PURPOSE: A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with etanidazole altered carboplatin pharmacokinetics. METHODS AND MATERIALS: Patients received 2 g/m2 of intravenous etanidazole followed by a second dose of 4 g/m2 90 min later, followed by intravenous carboplatin (300 mg/m2) and cyclophosphamide (600 mg/m2) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without etanidazole. RESULTS: Two patients who received a total of 24 g/m2 of etanidazole developed Grade 1 neurotoxicity, and therefore etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with etanidazole than after those without (p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t1/2 alpha and t1/2 beta for carboplatin were prolonged after pretreatment with etanidazole. CONCLUSION: Etanidazole, 2 g/m2 followed by 4 g/m2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of etanidazole, and an interaction between etanidazole and carboplatin may have enhanced neurotoxicity in these patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Induction of a 70 kD protein associated with the selective cytotoxicity of beta-carotene in human epidermal carcinoma.

Beta-carotene and canthaxanthin at concentrations of 70 or 300 microM were shown to inhibit the proliferation of cultured human squamous cells (SK-MES lung carcinoma and SCC-25 oral carcinoma) in a 5 hr cell density assay. Responses were similar for both tumor cell lines, ranging from 71-84% inhibition. In contrast, equimolar concentrations of alpha-tocopherol gave only 19-36% inhibition of SCC-25, but 50-75% inhibition of SK-MES cell density. Equimolar reduced glutathione resulted in 4-15% stimulation of SCC-25 and 22-25% inhibition of SK-MES cell proliferation. With cultured normal keratinocytes, treated final cell densities did not differ significantly from those of controls. Two additional assays measuring the metabolic generation of formazan (MTT assay) and [5-3H]thymidine incorporation were in substantial agreement with the growth inhibition pattern. Thus both continuous and cyclic cellular processes are involved in the tumor-specific response. Onset of the response to beta-carotene alone or in combination with alpha-tocopherol is signalled within 1-2 hours of treatment by the appearance of a unique 70 kD heat-shock protein.

Canthaxanthin↗

PubMed1989

Bone marrow autotransplantation for solid tumors--prospects.

Autologous bone marrow transplantation (AuBMT) is in clinical trial for patients with metastatic solid tumors, particularly breast cancer. This review deals with the potential of this approach. AuBMT is curative for the leukemias and lymphomas. Curative cancer chemotherapy has, almost without exception, required combinations of agents wherein dose was well maintained. However, curative chemotherapy strategies for the hematologic neoplasms have not proven successful for the common solid tumors. An important exception is that standard adjuvant chemotherapy can "cure" some micrometastatic tumors. Preclinical studies indicate the effectiveness of alkylating agents in terms of maintained dose effect through multiple logs of tumor cell kill; difficulty in developing drug resistance; general lack of cross resistance; and synergy for alkylating agents used in combination. There is an increasingly effective experimental basis for the construct of intensification regimens employing combinations of alkylating agents. Differing nonmyelosuppressive toxicity for alkylating agents provides a basis for maintaining dose when employed in combination in the autologous marrow situation. The aforementioned studies and cytokinetic analyses of combined intensive alkylating agent therapy for breast cancer support the potential of this approach. Clinical trials indicate a high response rate in refractory breast cancer. Trials involving induction chemotherapy followed by combined alkylating agent intensification have produced substantial complete remission rates. The duration of response has, in most studies, been short. This approach is associated with major toxicity, including mortality, and is expensive. Experimental and preliminary clinical evidence as marshalled in this review indicate that this is a promising area for therapeutic research.

Antineoplastic Agents↗

PubMed1988

Cyclophosphamide and thiotepa with autologous bone marrow transplantation in patients with solid tumors.

Autologous bone marrow transplantation to avoid dose-limiting myelosuppression may allow significant drug dose escalations and exploitation of the linear-log correlation between chemotherapy and tumor cytotoxicity. In a phase I trial of cyclophosphamide and thiotepa (with subsequent addition of melphalan), 23 patients were entered; there were two deaths due to toxic effects. The maximum tolerated dose was 6 g of cyclophosphamide/m2 and 720 mg of thiotepa/m2. No significant dose of melphalan could be added. Stomatitis was dose limiting. Eleven of 20 patients who were able to be evaluated responded. Plasma thiotepa concentrations correlated more closely with toxicity and response than with drug dose level. Continuous infusion cyclophosphamide and thiotepa is an active core regimen for the further design of high-dose combination chemotherapy regimens.

Adult↗

PubMed1986

The effect of chemotherapeutic agents on human oral squamous cell carcinoma transplanted to nude mice: a histologic study.

Clearly differentiated squamous cell carcinomas were transplanted to the backs of nude mice; tumor cells of a human tongue carcinoma cell line were used. Animals bearing tumors that measured at least 4 mm in diameter were treated with either methotrexate (MTX), cis-diamminedichloroplatinum II (CDDP) or bleomycin intraperitoneally for 5 days. Histologic evaluation of tumors obtained 24 hours after the last injection revealed degenerative and necrotic morphology in all treatment groups. The histologic alterations were observed prior to any clinical evidence of tumor shrinkage. The most impressive changes were found in CDDP-treated tumors, with creation of large pseudocysts containing necrotic material and cell debris. Pseudocyst formation was less obvious in MTX-treated animals and was absent in bleomycin-treated tumors. Drug treatment had no obvious influence on the keratinization in tumors. The findings suggest that the nude mouse model may be useful for the histologic determination of drug-induced effects on tumors in human beings.

Animals↗

PubMed1986

A clinical trial of Fluosol DA 20% in advanced squamous cell carcinoma of the head and neck.

Fluosol DA 20% (Fluosol) enhances the response of several rodent tumors to radiation and oxygen. This is a Phase I/II study of Fluosol and oxygen breathing in the radiation treatment of advanced squamous cell carcinoma of the head and neck. Fifteen patients with Stage III/IV tumors entered and completed this trial. Patients received 1.8 Gy/fraction to 45 Gy, at which time the spinal cord was shielded and gross disease was carried to 68-72 Gy. 8 ml/kg (11 patients) or 9 ml/kg (4 patients) Fluosol was infused prior to the first fraction each week for the first 5 weeks. All patients inspired 100% oxygen before and during the initial 25 fractions. The infusions were well-tolerated. Four acute reactions that responded to diphenhydramine or steroids were observed in the 75 infusions. 8/15 patients exhibited liver function abnormalities of 2-3X normal which fell after therapy was discontinued. Normal mucosal reactions were enhanced despite the 1.8 Gy fraction size. 10/15 patients required at least one treatment break: the mean dose achieved before the break was 35 Gy. Tumor clearance was also accelerated. Thirteen patients had primary tumor clearance, but one had a local recurrence. Ten had primary and nodal clearance and 2/3 with nodal persistence had salvage surgery with fibrosis only at pathologic review. One patient, locally controlled, developed distant metastases. Thus, 10/15 patients are NED, but followup time is short.

Carcinoma, Squamous Cell↗

PubMedDate not supplied

In vivo 19F NMR imaging.

In vitro and in vivo 19F spectra and images were obtained using various clinically safe fluorinated compounds. Standard and chemical shift images were acquired in solutions of fluorinated anesthetics with the chemical shift images clearly separating signals arising from a mixture of halothane and methoxyflurane. The 19F images of halothane in rats were unsuccessful at anesthetic concentration. In vivo 19F nuclear magnetic resonance (NMR) images were acquired at 57.9 MHz in rats receiving chronic injections of 14% perfluorodecalin, 6% perfluorotripropylamine (Fluosol-DA). The liver accumulates Fluosol-DA in the reticuloendothelial cells to concentrations that allow images to be obtained in less than 30 min. Image intensity from the perfluorochemicals reflects reticuloendothelial cell activity and thus is a functional image. Conventional proton NMR images at corresponding levels confirmed that the 19F signal arose from the liver and not muscle or fat. The 19F NMR images of the large bowel and stomach in rats were obtained by filling the lumen with concentrated Fluosol-DA. High contrast anatomical images showing gross structure of the gastrointestinal tract were acquired in as little as 12 min. These data suggest that 19F NMR may have a potential role in clinical imaging.

Abdomen↗

PubMedDate not supplied

Efficient lipofection with cisplatin-resistant human tumor cells.

Seven of seven different cisplatin-resistant human tumor cell lines showed elevated lipofection activity as compared with their sensitive parent cells, although the degree of enhancement was not quantitatively correlated with the degree of cisplatin resistance. Enhanced transfection was seen by using the same reporter gene driven by three different promoter/enhancer sequencer or by using different reporter genes driven by the same promoter/enhancer. Cells resistant to actinomycin D, bleomycin, and nitrogen mustards were not more transfectable than the sensitive parent cells. Although the mechanism of enhanced transfection in cisplatin-resistant cells is not known, data indicated that enhanced transcription, multidrug-resistant phenotype, and methallothionein overexpression do not play a role.

Chloramphenicol O-Acetyltransferase↗