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L Milas

Publications and source records attributed to L Milas.

At least 37 records · Page 2Linked to original sources
PubMed2000

In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody.

Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to cytotoxic agents, including radiation (T. Akimoto et al., Clin. Cancer Res., 5: 2884-2890, 1999), and thus is a candidate target for anticancer treatment. This study investigated whether treatment with C225 anti-EGFR antibody would improve tumor response to radiotherapy. Nude mice bearing 8-mm-diameter A431 tumor xenografts in the hind leg were treated with C225 antibody, 18 Gy of single-dose local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation or 6 h before and 3 and 6 days after irradiation. Delay in tumor growth was the treatment end point. C225 dramatically improved the efficacy of local tumor irradiation, particularly when multiple injections of C225 were administered. Tumor radioresponse was enhanced by a factor of 1.59 by a single dose and by a factor of 3.62 by a doses of C225. Histological analyses of tumors revealed that C225 caused a striking increase in central tumor necrosis associated with hemorrhage and vascular thrombosis when combined with radiotherapy. In addition, C225 induced heavy tumor infiltration with granulocytes, increased tumor cell terminal differentiation, and inhibited tumor angiogenesis. We conclude that C225 anti-EGFR antibody enhances tumor radioresponse by multiple mechanisms that may involve direct and indirect actions on tumor cell survival.

Animals↗
PubMed2000

Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor.

The antitumor effects of the selective cyclooxygenase (COX)-2 inhibitor SC-236 alone and in combination with radiation were investigated using the human glioma cell line U251 grown in monolayer culture and as tumor xenografts. On the basis of Western and Northern blot analyses, these cells express COX-2 protein and mRNA to levels similar to those in the human colon carcinoma cell line HT29. Treatment of U251 cells in monolayer culture with 50 microM SC-236 resulted in a time-dependent decrease in cell survival as determined by a clonogenic assay. The cell death induced by SC-236 was associated with apoptosis and the detachment of cells from the monolayer. After 2 days of drug treatment, the cells that remained attached were exposed to graded doses of radiation, and the clonogenic assay was performed. Comparison of the survival curves for drug-treated and untreated cultures revealed that SC-236 enhanced radiation-induced cell death. In these combination studies, SC-236 treatment resulted in a dose-enhancement factor of 1.4 at a surviving fraction of 0.1, with the surviving fraction at 2 Gy (SF2) reduced from 0.61 to 0.31. These data indicate that in vitro SC-236 induces U251 apoptotic cell death and enhances the radiosensitivity of the surviving cells. To extend these investigations to an in vivo situation, U251 glioma cells were grown as tumor xenografts in the hind leg of nude mice, and SC-236 was administered in drinking water. SC-236 alone slowed tumor growth rate, and when administered in combination with local irradiation, SC-236 caused a greater than additive increase in tumor growth delay. These in vitro and in vivo results suggest that the selective inhibition of COX-2 combined with radiation has potential as a cancer treatment.

Animals↗
PubMed2000

Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy.

The poly(L-glutamic acid)-paclitaxel (PG-TXL) conjugate has been shown to exhibit significantly greater antitumor activity than conventionally formulated paclitaxel (TXL) against solid tumors (Li et al., Cancer Res., 58: 2404-2409, 1998). Here we report that local tumor irradiation enhanced the distribution of PG-TXL given 24 h later to ovarian OCa-1 carcinoma implanted i.m. in C3Hf/Kam mice. Radiation significantly increased tumor uptake of PG-TXL and tumor vascular permeability, caused elevation of the serum concentration of vascular endothelial growth factor, and arrested OCa-1 cells in the G1 phase of cell cycle. The enhancement factors, as measured by incremental tumor growth delay compared with PG-TXL alone, ranged from 1.36-4.44. Complete tumor regression was also observed at a higher radiation dose (>10 Gy) and a higher PG-TXL dose (>80 mg equivalentTXL/kg). Furthermore, combined radiation and PG-TXL produced a significantly greater tumor growth delay than treatment with radiation and TXL when both drugs were given at the same equivalent TXL dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50). These data suggest that conjugation of TXL to poly(L-glutamic acid) is necessary for improved response and that the supra-additive effect of combined radiation and PG-TXL therapy is due in part to modulation of the enhanced permeability and retention effect of macromolecules by radiation. We propose a treatment strategy combining radiation and macromolecular chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.

Animals↗
PubMed2000

[Recent studies on anti-angiogenesis in cancer therapy].

Angiogenesis is known to be a critical process for the tumor growth and metastasis. There are many indigenous role-players in tumor angiogenesis and anti-angiogenesis, where tumor-host interaction may work. A lot of agents with anti-angiogenic activity have been developed for anti-cancer treatment. Several agents including Marimastat, Primostat, Neovastat, Bay-12-9566m, Interferon-alpha, SU101, retinoids, and IM862, are/were under phase-three study. There are still many future-promising results of basic or clinical studies on inhibitors of MMPs, and inhibitors of VEGF/R, Endostatin, somatostatin analogues, COX-2 inhibitors, and others. Most of the combination treatments of antiangiogenetic agent and conventional anticancer agents therapy, or radiation therapy as we reported, showed relatively small or minute increase in toxicity of these cytotoxic treatments.

Angiogenesis Inhibitors↗
PubMed1999

Effectiveness of accelerated radiotherapy for patients with inoperable non-small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review.

PURPOSE: The standard treatment for patients with unresectable or medically inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g., weight loss [WL] < or = 5% and Karnofsky performance status [KPS] > or = 70) is induction chemotherapy followed by definitive radiotherapy to the primary site at 1.8-2.0 Gy per fraction with a total dose of 60-63 Gy to the target volume. Patients with poor prognostic factors usually receive radiotherapy alone, but the fractionation schedule and total dose have not been standardized. To attempt to optimize irradiation doses and schedule, we compared the effectiveness of accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard radiation therapy (STRT) of 60-66 Gy at 2 Gy per fraction in regard to tumor response, local control, distant metastasis, toxicity, and survival. METHODS AND MATERIALS: Fifty-five patients treated with radiation for NSCLC at The University of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All 55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two cohorts were identified. One cohort (26 patients) had borderline poor prognostic factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT). The second cohort (29 patients) had significantly better prognostic factors (KPS > or = 70 and WL < or = 5%) and was treated to 60-66 Gy over 6 to 6 1/2 weeks at 2 Gy per fraction (STRT) during the same period. RESULTS: In the first cohort treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%, and IIIB 73%. Sixty-two percent had KPS <70, and 76% had a WL of >5%. The maximum response rate as determined by chest X-ray was 60% among 45 of 55 patients who were evaluable for response: combined complete responses (20%) and partial responses (40%). Overall survival in these patients was 13% at 2 and 5 years, with a locoregional control rate of 42% and a freedom from distant metastasis rate of 54%. The ACRT cohort treated with 3 Gy per fraction had significantly lower KPS scores (p = 0.003) and greater WL (p = 0.063) than the cohort STRT treated with 2 Gy per fraction. However, treatment results and toxicity were not significantly different between the two cohorts in spite of significantly better prognostic factors in the STRT cohort. CONCLUSIONS: Despite having worse prognostic factors, the cohort treated with radiotherapy alone to 45 Gy at 3 Gy per fraction over 3 weeks (ACRT) had response rates, locoregional control, and overall survival comparable to those in the cohort treated by a total dose of 60-66 Gy at 2 Gy per fraction over 6 to 6 1/2 weeks (STRT). Given that accelerated treatment schedules decrease treatment time and cost less, these may, in the current health care environment, be important factors for health care providers to consider in treating patients who have locally advanced NSCLC and borderline poor prognostic factors.

Carcinoma, Non-Small-Cell Lung↗
PubMed1999

Maximizing therapeutic gain with gemcitabine and fractionated radiation.

PURPOSE/OBJECTIVE: The nucleoside analogue gemcitabine inhibits cellular repair and repopulation, induces apoptosis, causes tumor growth delay, and enhances radiation-induced growth delay. After single doses of drug and radiation, maximum enhancement of tumor response was obtained when gemcitabine preceded radiation by at least 24 h. Conversely, the cellular radioresponse of the normal gastrointestinal epithelium was slightly protected when gemcitabine and radiation were separated by 24 h. This differential response created a time frame within which therapeutic gain could be maximized. In our present investigation, we sought to define the most therapeutically beneficial scheme of gemcitabine administration when combined with fractionated radiotherapy. METHODS AND MATERIALS: C3Hf/Kam mice were given identical drug and radiation schedules of administration, and both normal tissue (jejunal mucosa) and tumor (Sa-NH) responses were measured. Irradiation was given once per day for 5 days in normal tissue and tumor growth delay studies and twice per day for the tumor cure endpoint. A total dose of 25 mg/kg gemcitabine was given i.p. in 1 of 3 schedules: a single dose of 25 mg/kg 24 h before the start of fractionated irradiation, 12.5 mg/kg 24 h before the first and third radiation doses, or 24 h before each of 5 radiation doses. Groups of mice bearing 7- or 8-mm diameter tumors were treated with gemcitabine alone or in combination with fractionated irradiation under ambient or hypoxic conditions. The survival response of the jejunal mucosa was quantified by the microcolony assay and histologically by quantifying apoptosis, mitosis, S-phase fraction, and crypt cellularity. RESULTS: For tumor growth delay, dose-modifying factors (DMFs) were similar (1.34-1.46) for all 3 schedules of drug administration. In contrast, the response of the jejunum was strongly dependent on the schedule of gemcitabine administration. A single dose of gemcitabine before the start of fractionated radiotherapy resulted in slight radioprotection (DMF 0.96). Two doses and 5 daily doses of gemcitabine enhanced radiation response by factors of 1.09 and 1.23, respectively. Major factors affecting the response of the jejunal mucosa were apoptotic death of S-phase cells exposed to gemcitabine and cell cycle synchrony of surviving cells. Tumor reoxygenation was found to be a major mechanism for tumor radioenhancement, in addition to those reported earlier. CONCLUSION: All 3 schedules of drug administration produced therapeutic gain; however, when gemcitabine was given more than once in a 5-fraction radiation treatment schedule, normal tissue toxicity increased. The highest therapeutic gain (1.4) was achieved by giving a single dose of gemcitabine (25 mg/kg) 24 h before the start of fractionated radiotherapy.

Animals↗
PubMed1999

Association of increased radiocurability of murine carcinomas with low constitutive expression of p21(WAF1/CIP1) protein.

PURPOSE: The study investigated whether basal, constitutive levels of p21(WAF1/CIP1) protein in murine carcinomas are related to in vivo tumor radioresponse. The study is based on recent observations demonstrating that in vitro cancer cell lines are resistant to cytotoxic drugs when they express high basal levels of p21(WAF1/CIP1) protein, and that the loss of the p21 gene in the HCT116 human colorectal cancer cell line results in increased radioresponse of xenografts derived from that cell line. METHODS AND MATERIALS: Protein levels of p21(WAF1/CIP1), p53, bax, and bcl-2 were determined in 8 carcinomas (3 mammary carcinomas designated MCa-4, MCa-29, and MCa-35, 2 squamous cell carcinomas designated SCC-IV and SCC-VII, ovarian adenocarcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG) syngeneic to C3Hf/Kam mice using Western blot analysis. The tumors, growing in the right hind legs of mice, were 8 mm in diameter at the time of analysis. These tumors greatly differ in their radioresponse, assessed by TCD50 assay, and in their susceptibility to radiation-induced apoptosis. RESULTS: Protein levels of these oncogenes varied among tumors, with p21(WAF1/CIP1) showing the greatest variation: its mean densitometric value ranged from 1 to 19. Bcl-2 levels also showed broad variation in densitometric values, from 1 to 10. In comparison, bax and p53 (7 of 8 tumors contained wild-type p53) varied much less among different tumor types; their variation was within a 5-fold range, and the level of p53 was similar in 6 of 8 tumors. Tumor radioresponse correlated significantly (R = 0.77, p = 0.02) only with the magnitude of p21(WAF1/CIP1)expression: tumors with high levels of p21(WAF1/CIP1)were less radiocurable than those with lower levels. Tumor radiocurability showed a significant positive correlation (p = 0.02) with the extent of radiation-induced apoptosis, indicating that tumors that responded to radiation with higher percentages of apoptosis were more curable by radiation. Despite a strong trend to correlation, (p = 0.15), p21(WAF1/CIP1) expression did not correlate significantly with radiation-induced apoptosis, which suggested that p21(WAF1/CIP1) influenced tumor radioresponse by mechanisms beyond that of apoptosis induction. CONCLUSION: Our findings showed that murine tumors exhibit wide variation in constitutive levels of p21(WAF1/CIP1) which had a significant relationship with tumor radioresponse: tumors with high levels of p21(WAF1/CIP1) were less radiocurable than those with lower levels. These findings support the concept that p21(WAF1/CIP1) is a major determinant of tumor radioresponse in vivo, and may have important clinical implications. The pretreatment assessment of p21(WAF1/CIP1) protein could serve as a useful predictor of radiotherapy outcome and may assist in selecting an effective treatment modality.

Animals↗
PubMed1999

Apoptosis and the Bcl-2 gene family -- patterns of expression and prognostic value in stage I and II follicular center lymphoma.

PURPOSE: The prognostic significance of spontaneous levels of apoptosis and Bcl-2, Bax, and Bcl-x protein expression in follicular center lymphoma (FCL) is unknown. The objectives of this retrospective study were (1) to investigate the relationship between pretreatment apoptosis levels and long-term treatment outcome in patients with Stage I and II FCL; (2) to define the incidence and patterns of Bax and Bcl-x protein expression in human FC; and (3) to determine the relationship of Bcl-2, Bax, and Bcl-x expression with spontaneous apoptosis levels and clinical outcome in localized FCL. METHODS AND MATERIALS: Between 1974 and 1988, 144 patients with Stage I or II FCL were treated. Hematoxylin and eosin (H & E) stained tissue sections of pretreatment specimens were retrieved for 96 patients. Treatment consisted of regional radiation therapy (XRT) for 25 patients, combined modality therapy (CMT) consisting of combination chemotherapy and XRT for 57 patients, and other treatments for 14 patients. Median follow-up for living patients was nearly 12 years. The apoptotic index (AI) was calculated by dividing the number of apoptotic cells by the total number of cells counted and multiplying by 100. Expression of Bcl-2, Bax, and Bcl-x proteins was assessed using immunohistochemistry. RESULTS: The mean and median AI values for the entire group were 0.53 and 0.4, respectively (range: 0-5.2). The AI strongly correlated with cytologic grade, with mean AI values of 0.25 for grade 1, 0.56 for grade 2, and 0.84 for grade 3 (p < 0.0005; Kendall correlation). A positive correlation was present between grouped AI and grouped mitotic index (MI) (p = 0.014). For patients treated with CMT, an AI < 0.4 correlated with improved freedom from relapse (FFR) p = 0.0145) and overall survival (OS) (p = 0.0081). An AI < 0.4 did not correlate with clinical outcome for the entire cohort or for patients receiving XRT only. Staining of tumor follicles for the Bcl-2 protein was positive, variable, and negative in 73%, 15%, and 12% of cases, respectively. Positive staining of tumor follicles was observed in 96% of cases for both the Bax and Bcl-x proteins. Expression of Bcl-2, Bax, or Bcl-x did not correlate with AI or clinical outcome. CONCLUSION: The level of spontaneous apoptosis in pretreatment specimens correlates with cytologic grade of FCL and is a significant predictor of FFR and OS for patients with localized FCL receiving CMT.

Analysis of Variance↗
PubMed1999

Enhancement of tumor radioresponse in vivo by gemcitabine.

Gemcitabine, 2'2'-difluoro-2'-deoxycytidine, is an inhibitor of DNA synthesis and has been shown previously in vitro and in vivo to enhance the cytotoxic activity of radiation as well as some chemotherapeutic agents. Because gemcitabine has shown clinical activity on its own in several solid tumors traditionally treated with radiotherapy, it was of interest to optimize the combination of gemcitabine and radiation. To determine the optimal gemcitabine dose to combine with irradiation and to determine the effect of gemcitabine on tumor growth, mice bearing SA-NH tumors were treated with 2.5 to 600 mg/kg gemcitabine, and subsequent tumor growth was determined. At low doses, gemcitabine induced transient growth delay, whereas higher doses showed both cytotoxic and cytostatic activity. Flow cytometric, histological, and mitotic analyses of irradiated tumors showed that gemcitabine induced a dose-dependent inhibition of DNA synthesis and induction of apoptosis of cells in S phase. DNA synthesis recovered in cells at the G1-S boundary of the cell cycle in a dose-dependent manner, and a parasynchronous movement of cells through the cell cycle ensued. To determine the optimal schedule for gemcitabine administration in relation to irradiation, tumor-bearing mice were given a single 50 mg/kg dose of gemcitabine at various times before or after irradiation. Gemcitabine enhanced radioresponse in a time-dependent fashion. The highest enhancement factors for tumor growth delay (1.68-2.03) were observed when gemcitabine was administered 24-60 h before irradiation. Although gemcitabine reduced the radiation tumor control dose at all administration times used, the greatest enhancement of tumor radiocurability occurred when gemcitabine was administered 24 h before irradiation (dose modification factor of 1.54). Moreover, gemcitabine decreased the lung metastatic rate in mice with local tumor control from 73% in mice receiving radiation alone to 40% in mice receiving the combination (all combination times included). These results suggest that gemcitabine has strong radioenhancing properties and that the greatest interaction occurs when gemcitabine administration precedes irradiation by 24-72 h. Preliminary studies indicate that normal tissues recover more quickly than tumor tissues from gemcitabine treatment; thus, optimized scheduling of gemcitabine and irradiation may serve to improve the therapeutic ratio of the combination.

Animals↗
PubMed1999

Evaluation of In-111 DTPA-paclitaxel scintigraphy to predict response on murine tumors to paclitaxel.

UNLABELLED: Our goal was to determine whether scintigraphy with 111In-DTPA-paclitaxel could predict the response to chemotherapy with paclitaxel. METHODS: Ovarian carcinoma (OCA 1), mammary carcinoma (MCA-4), fibrosarcoma (FSA) and squamous cell carcinoma (SCC VII) were inoculated into the thighs of female C3Hf/Kam mice. Mice bearing 8 mm tumors were treated with paclitaxel (40 mg/kg). The growth delay, which was defined as the time in days for tumors in the treated groups to grow from 8 to 12 mm in diameter minus the time in days for tumors in the untreated control group to reach the same size, was measured to determine the effect of paclitaxel on the tumors. Sequential scintigraphy in mice bearing 10 to 14 mm tumors was conducted at 5, 30, 60, 120, 240 min and 24 hrs postinjection of 111In-DTPA-paclitaxel (3.7MBq) or 111In-DTPA as a control tracer. The tumor uptakes (% injection dose/pixel) were determined. RESULTS: The growth delay of OCA 1, MCA-4, FSA and SCC VII tumors was 13.6, 4.0, -0.02 and -0.28 days, respectively. In other words, OCa 1 and MCA-4 were paclitaxel-sensitive tumors, whereas FSA and SCC VII were paclitaxel-resistant tumors. The tumor uptakes at 24 hrs postinjection of In-111 DTPA paclitaxel of OCA 1, MCA-4, FSA and SCC VII were 1.0 x 10(-3), 1.6 x 10(-3), 2.2 x 10(-3) and 9.0 x 10(-3) % injection dose/pixel, respectively. There was no correlation between the response to chemotherapy with paclitaxel and the tumor uptakes of 111In-DTPA-paclitaxel. CONCLUSIONS: Scintigraphy with 111In-DTPA-paclitaxel could not predict the response to paclitaxel chemotherapy. Although there was significant accumulation of the paclitaxel in the tumor cells, additional mechanisms must be operative for the agent to be effective against the neoplasm. 111In-DTPA-paclitaxel activity is apparently different from that of paclitaxel with Cremophor.

Animals↗
PubMed1999

Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel.

PURPOSE: To determine, as we did for paclit-axel, whether mitotic arrest and apoptosis induced in murine tumors in vivo by docetaxel correlate with the drug's antitumor effect and whether the antitumor efficacy of docetaxel depends on p53 mutational status of tumors. METHODS: C3Hf/Kam mice were implanted with one of the following 15 syngeneic tumors: seven adenocarcinomas (MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VII), five sarcomas (FSa, FSa-II, Sa-NH, NFSa, and Sa-4020) and one lymphoma (Ly-TH). When the tumors had grown to 8 mm in diameter, the mice were treated with 31.3 mg/kg docetaxel i.v. Tumor growth delay was the endpoint of docetaxel's antitumor effect. In separate groups of mice, mitotic arrest and apoptosis were determined micromorphometrically 1 to 72 h after docetaxel treatment. Tumors were assayed for their p53 status by sequence analysis of RNA prepared from freshly excised tumors. RESULTS: Docetaxel caused statistically significant growth delay in six of seven adenocarcinomas, three of five sarcomas, and the lymphoma, but not in either of the squamous cell carcinomas. The drug induced mitotic arrest in all tumor types, but to various degrees ranging from 6.4+/-0.4% to 25.1+/-0.1%. In contrast, docetaxel induced appreciable apoptosis in only 5 of 15 tumors, with 10.3+/-1.6% being the highest apoptotic value. Neither mitotic arrest nor apoptosis were significantly correlated with tumor growth delay. However, tumors that responded to docetaxel by significant tumor growth delay histologically displayed massive cell destruction by cell lysis, and four of these tumors also showed marked infiltration with mononuclear lymphoid cells. Of the 15 tumors only 3 had mutant p53. CONCLUSIONS: Docetaxel exhibited a strong antitumor effect in two-thirds of murine tumors, and on a milligram per kilogram basis was more effective than paclitaxel against the same tumors. The drug was a potent inducer of mitotic arrest but a weak inducer of apoptosis, neither of which correlated with its antitumor effect. Tumor cell lysis appeared to be a major mode of tumor cell destruction and can be regarded as the main mechanism underlying antitumor efficacy of docetaxel. In contrast, paclitaxel's antitumor efficacy is related to its ability to induce apoptosis. At the molecular level, there was no dependency of antitumor efficacy of docetaxel on p53 mutational status of tumors.

Animals↗
PubMed1999

[Inhibition of tumor neo-angiogenesis and induction of apoptosis as properties of docetaxel (taxotere)].

Paclitaxel and docetaxel are potent drugs that are effective in the treatment of malignant tumors. The cytotoxic action of these drugs is not fully understood, but it appears to be mediated mainly through mitotic arrest and subsequent apoptosis. Because no information is available on the antiangiogenesis action of docetaxel, the investigations were performed to determine whether inhibition of neoangiogenesis plays a role in docetaxel's antitumor efficacy. Four different mouse tumors, two squamous cell carcinomas (SCC-IV; SCC-VII) and two adenocarcinomas (MCA-4; MCA-29) were assayed for angiogenic activity using the in vivo i.c. angiogenesis assay. Tumor cells (5 x 10(5)) were injected i.c. into the skin flap over the abdominal wall, and the number of new blood vessels at the tumor cell injection site was determined 2, 4, 6, 8, 10 and 12 days later. The mice were treated with docetaxel (Taxotere--31.3 mg/kg i.v.) 1 or 4 days after tumor cell injection. The number of new blood vessels increased with time. Docetaxel reduced the number of newly formed blood vessels in MCAs, but not in SCCs. The reduction was associated with slower tumor growth. In a separate set of experiments we observed that docetaxel's inhibitory effect on the two MCAs was histologically associated with massive tumor cell destruction by means of both apoptosis and necrosis. This was not observed for the two SCCs. Since no reduction in blood vessels occurred in tumors unresponsive to docetaxel, the inhibition of neoangiogenesis in docetaxel-responsive tumors was likely the result of a decrease in angiogenic stimuli due to docetaxel's destruction of tumor cells.

Adenocarcinoma↗
PubMed1999

Low E-cadherin and beta-catenin expression correlates with increased spontaneous and artificial lung metastases of murine carcinomas.

This study examined the relationship between the expression of E-cadherin or beta-catenin in murine adenocarcinomas and their hematogenous metastatic propensity, assessed by both spontaneous and artificial lung metastasis. Seven different carcinomas, syngeneic to C3Hf/Kam mice were used: 4 mammary carcinomas (MCa-4, MCa-29, MCa-35, and MCa-K), ovarian carcinoma OCa-I, hepatocarcinoma HCa-I, and adenosquamous carcinoma ACa-SG. These tumors vary widely in their ability to spontaneously metastasize to the lung (from 0 to 100% metastatic incidence), and their cells greatly differ in their ability to form artificial lung nodules when injected i.v. Primary tumors in the leg were assessed for E-cadherin and beta-catenin expression by western blotting. The expression of both proteins showed wide variation among the tumors; however, the expression of E-cadherin correlated well with that of beta-catenin. There was significant inverse correlation between the expression of E-cadherin, as well as beta-catenin, and the incidence of both spontaneous and artificial lung metastases from these tumors. Spontaneous metastases of highly metastatic HCa-I and moderately metastatic MCa-35 were significantly lower in E-cadherin and beta-catenin expression than their corresponding primary tumors were. Thus, the propensity of murine carcinomas for hematogenous spread is highly related to E-cadherin and beta-catenin levels in primary tumors. The inverse correlation between the expression of these molecules and spontaneous and artificial metastases implies that tumor cells with low E-cadherin and beta-catenin content have increased ability to enter the vascular circulation at the primary tumor site and to colonize distant tissues.

Adenocarcinoma↗
PubMed1999

Refractory arthropathy after intravesical bacillus Calmette-Guérin therapy. Usefulness of isoniazide.

BACKGROUND: Arthritis associated with bacillus Calmette-Guérin immunotherapy usually responds dramatically to nonsteroidal antiinflammatory drug therapy. Isoniazid is generally reserved for other complications such as granulomatous hepatitis. CASE-REPORT: A 73-year-old man was admitted for fever, arthritis of the knees and right temporomandibular joint, an inflammatory swelling over the left Achilles tendon and bilateral conjunctivitis. The symptoms started in the wake of a course of intravesical bacillus Calmette-Guérin immunotherapy. Laboratory tests showed evidence of severe inflammation. Cultures of blood, urine and joint fluid specimens were negative, as were tests for autoantibodies and serologic tests for organisms known to cause reactive arthritis. Nonsteroidal antiinflammatory therapy was ineffective and glucocorticoid therapy produced only a partial response. All the symptoms resolved under isoniazid therapy in a dosage of 300 mg/day for three months. CONCLUSION: Use of antituberculous agents may be required in some cases of arthritis associated with bacillus Calmette-Guérin immunotherapy, most notably those with severe pyrexia.

Adjuvants, Immunologic↗
PubMed1999

Combination of taxanes with radiation: preclinical studies.

Treatment regimens consisting of taxanes, a potent class of chemotherapeutic agents, combined with radiotherapy have recently undergone extensive preclinical investigation. The focus was primarily on cell radiosensitization because taxanes arrest cells in the radiosensitive G2/M phase of the cell cycle. In vitro studies provided ample evidence that taxanes can enhance radiation sensitivity of tumor cells, with enhancement factors ranging from 1. 1 to more than 3.0. Additive or subadditive effects were also reported. The outcome of the taxane-radiation interaction in vitro depended on many factors, including cell type, proliferation state of cells, drug concentration, and timing of radiation delivery in relation to drug administration. In vivo studies, although limited, showed that taxanes can strongly enhance tumor radioresponse, producing enhancement factors of 1.2 to more than 2.0. Two major mechanisms of tumor radioenhancement were detected: reoxygenation of radioresistant hypoxic cells and G2/M arrest. Both occur in tumors that respond to taxanes by mitotic arrest and apoptosis. Only G2/M arrest occurs in tumors that display only mitotic arrest. Compared with tumor radioresponse, normal tissue radioresponse was much less affected by taxanes. On a molecular level, taxanes activate a number of genes, but it appears that their effects are mainly p53-independent and primarily involve phosphorylation of the Bcl-2 gene. Overall, preclinical studies show that taxanes can enhance radiation sensitivity of tumor cells, potentiate tumor response, and increase the therapeutic ratio of radiotherapy. The cellular and molecular effects of taxanes may be useful in designing optimal treatment schedules for clinical trials.

Animals↗
PubMed1999

Antitumor activity of poly(L-glutamic acid)-paclitaxel on syngeneic and xenografted tumors.

Poly(L-glutamic acid)-paclitaxel (PG-TXL) is a new water-soluble paclitaxel derivative that has shown remarkable antitumor activity against both ovarian and breast tumors. The purpose of this study was to test whether the antitumor efficacy of PG-TXL depends on tumor type, as is the case for paclitaxel, and to test whether paclitaxel-resistant tumors could be responsive to PG-TXL. We evaluated the therapeutic activity of PG-TXL against four syngeneic murine tumors (MCa-4, MCa-35, HCa-1, and FSa-II) inoculated i.m. into C3Hf/Kam mice, a human SKOV3ip1 ovarian tumor injected i.p. into nude mice, and a human MDA-MB-435Lung2 breast tumor grown in the mammary fat pad of nude mice. Two paclitaxel-responsive murine tumors, MCa-4 and MCa-35, showed significant growth delay with PG-TXL given as a single i.v. injection at its maximum tolerated dose of 160 mg of equivalent paclitaxel/kg or even at a lower dose of 120 mg of equivalent paclitaxel/kg. The other two murine tumors, HCa-1 and FSa-II, did not respond particularly well to either of the two agents, although significant growth delay was observed for both tumors with PG-TXL. In mice with SKOV3ip1 tumors, the median survival times for mice treated with PG alone and PG-TXL at doses of 60 or 120 mg of equivalent paclitaxel/kg were 43, 61, and 75 days, respectively; no survival difference was found between paclitaxel-treated and Cremophor vehicle-treated mice. In mice with MDA-MB-435Lung2 tumor, PG-TXL at a dose of 120 mg of equivalent paclitaxel/kg produced regression of the tumor in 50% of the animals, and in the remaining mice, micrometastases in the lung were found only in 25% of the animals. In comparison, treatment with paclitaxel at 60 mg/kg did not result in tumor regression, and the rate of lung metastases was 42%. These results clearly demonstrate that PG-TXL has significant therapeutic activity against breast and ovarian tumors tested in this study. Future studies to elucidate the mechanism of action of PG-TXL and to assess its clinical applications are warranted.

Animals↗