Biomedical subjects

Luka Milas

Publications and source records attributed to Luka Milas.

At least 19 recordsLinked to original sources

PubMed2004

CpG oligodeoxynucleotide enhances tumor response to radiation.

CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences containing unmethylated cytosine-guanine motifs with potent immunomodulatory effects. Via Toll-like receptor 9 agonism of dendritic cells and B cells, CpG ODNs induce cytokines, activate natural killer cells, and elicit vigorous T-cell responses that lead to significant antitumor effects, including improved efficacy of chemotherapeutic agents. On the basis of these properties of CpG ODNs, we tested whether they also could enhance tumor response to radiotherapy. Using an immunogenic mouse tumor, designated FSa, the response to radiotherapy was assayed by tumor growth delay and tumor cure rate (TCD(50), radiation dose yielding 50% tumor cure rate). Treatments were initiated when established tumors were either 6 or 8 mm in diameter. CpG ODN as a single agent given s.c. peritumorally had little effect on tumor growth; however, it dramatically enhanced tumor growth delay in response to single-dose radiation by a factor of 2.58-2.65. CpG ODN also dramatically improved tumor radiocurability, reducing the TCD(50) by a factor of 1.93, from 39.6 (36.1-43.1) Gy to 20.5 (14.3-25.7) Gy. The CpG ODN-induced enhancement of tumor radioresponse was diminished in tumor-bearing mice immunocompromised by sublethal whole-body radiation. Tumors treated with CpG ODN and radiation showed histologic changes characterized by increased necrosis, heavy infiltration by host inflammatory cells (lymphocytes and granulocytes), and reduced tumor cell density. These results show that CpG ODNs are potent enhancers of tumor radioresponse and as such have potential to improve clinical radiotherapy.

Animals↗

PubMed2004

C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy.

PURPOSE: C225 anti-EGFR (epidermal growth factor receptor) antibody has been shown to enhance tumor response to radiation and a number of chemotherapeutic agents. Because of increased use of concurrent chemoradiotherapy in cancer treatment, it is important to determine whether C225 enhances also the antitumor efficacy of radiation when combined with chemotherapy. This study assessed the effect of C225 on tumor response when combined with docetaxel plus single or fractionated radiation. METHODS AND MATERIALS: MDA468 human adenocarcinoma and A431 human epidermoid carcinoma cells growing as xenografts in the right hind leg of nude mice were used. Mice bearing 8-mm tumors were treated with C225 antibody at a dose of 1 mg given i.p. once, twice, or three times 3 days apart, 10 or 30 mg/kg docetaxel given i.v., and/or local tumor irradiation of 8 or 10 Gy single dose or fractionated irradiation consisting of 2 Gy daily for 5 days. When all three agents were combined, C225 was given 6 h before or 18 h after docetaxel, and radiation was given 24 h after docetaxel. The treatment end point was tumor growth delay. RESULTS: C225 enhanced the antitumor efficacy of docetaxel, local tumor irradiation, and docetaxel combined with radiation. The response of both MDA468 and A431 carcinomas was enhanced. The enhancement factors ranged from 1.19 to 8.52, the degree of the enhancement depending on experimental conditions such as administration of multiple vs. single dose C225 or single or fractionated irradiation. C225 given twice or 3 times was more effective than when administered as a single dose. The effect of C225 was more pronounced when combined with single than fractionated irradiation with or without docetaxel. The triple-agent therapy was more effective than a single agent or double combination therapies, expressed by both increased tumor growth delay and the rate of tumor cure. CONCLUSIONS: Our results show that C225 anti-EGFR antibody is a potent enhancer of tumor response to docetaxel or radiation as single agents, and to docetaxel when combined with radiation. Thus, these findings provide strong preclinical evidence in support of combination of anti-EGFR blockade with chemoradiotherapy.

Animals↗

PubMed2004

Flavopiridol increases therapeutic ratio of radiotherapy by preferentially enhancing tumor radioresponse.

PURPOSE: Recently we reported that inhibition of cyclin-dependent kinases (cdks) by flavopiridol enhanced the radiation response of murine ovarian carcinoma cells in culture. The purpose of this investigation was to extend these studies to in vivo tumor models and test whether flavopiridol increases the therapeutic ratio of radiotherapy. METHODS AND MATERIALS: Three transplantable syngeneic mouse tumors were used: mammary carcinoma (MCa-29), ovarian carcinoma (OCa-I), and a lymphoma (Ly-TH). Tumor treatment endpoints included growth delay, cure, and spontaneous lung metastases (OCa-I tumor). The normal tissue endpoint was survival of jejunal crypt cells quantified microscopically. A range of flavopiridol doses from 0.625 to 5.0 mg/kg were given systemically once or twice daily over 5, 10, or 20 days. Combined therapy flavopiridol treatments were initiated either several days before or shortly after the start of single dose or daily fractionated radiotherapy. RESULTS: The major findings of this study are that all three tumors treated with flavopiridol alone responded by tumor growth delay. Two of the tumors (MCa-29 and Ly-TH) responded in a schedule-dependent manner with larger radiation enhancement factors when flavopiridol treatment was started a few hours after irradiation (radioenhancement factors [EF] Ly-TH = 2.04, EF MCa-29 = 1.50 for single dose irradiation). When combined with fractionated irradiation (2.6 Gy daily for 10 or 20 days), flavopiridol enhanced the response of the MCa-29 tumor by a factor of 1.25-1.46. A fractional radiation dose of 6 Gy in combination with flavopiridol produced a 62.5% cure rate compared with 25% tumor cure for radiation alone. A novel finding of this study was the demonstration of antimetastatic activity of flavopiridol in addition to its effect on the local primary tumor. Both the incidence and absolute number of lung metastasis were reduced when flavopiridol followed surgical removal of the large (10 mm) primary leg tumor. The normal jejunum treated with flavopiridol and radiation responded in a schedule independent manner and the degree of radioenhancement (EF, 1.05-1.06) was much less than for any of the tumors studied. CONCLUSIONS: Therapeutic gain was achieved when flavopiridol treatment was initiated either before or after the start of radiotherapy. Flavopiridol shows promising clinical potential administered alone or in combination with other cytotoxic agents, including both chemotherapy and radiotherapy.

Animals↗

PubMed2004

Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial.

PURPOSE: To determine the ability of amifostine to reduce the severity and/or incidence of the acute toxicities of concurrent chemotherapy and radiotherapy (RT) for non-small-cell lung cancer. METHODS AND MATERIALS: Patients with inoperable, nonmetastatic non-small-cell lung cancer receiving concurrent chemoradiotherapy were randomized to one of two treatment groups. Arm 1 patients received thoracic RT (total dose, 69.6 Gy in 58 fractions of 1.2 Gy b.i.d. 5 d/wk), plus oral etoposide (50 mg b.i.d. 30 min before thoracic RT for 10 days, repeated on Day 29) and cisplatin (50 mg/m2 i.v. on Days 1, 8, 29, and 36). Arm 2 patients received the same treatment plus amifostine (500 mg i.v. 20-30 min before any treatment the first 2 days of each week). Acute effects were assessed using the National Cancer Institute Common Toxicity Criteria. RESULTS: Sixty-two patients were enrolled between November 1998 and January 2001. The minimal follow-up was 24 months, and the median follow-up of living patients was 31 months. The patient and tumor characteristics were equally distributed between the patients in the two arms. The median survival time was 20 months in Arm 1 patients and 19 months in Arm 2 patients. The maximal esophageal toxicity was mild (Grade 1) in 23%, moderate (Grade 2) in 42%, and severe (Grade 3-4) in 35% of patients in Arm 1; the corresponding rates for the Arm 2 patients were 48%, 35%, and 16% (p = 0.021). Severe pneumonitis occurred in 16% of the Arm 1 and none of the Arm 2 patients (p = 0.020, chi-square test). Neutropenic fever occurred in 39% of Arm 1 and 16% of Arm 2 patients (p = 0.046, chi-square test). Mild hypotension, dysgeusia, and sneezing were significantly more frequent among the patients in Arm 2. CONCLUSION: Amifostine reduced the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and RT. Amifostine had no apparent effect on survival in these patients with unresectable non-small-cell lung cancer, suggesting that it does not have a tumor-protective effect.

Adult↗

PubMed2004

Radiosensitization of human and rodent cell lines by INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase.

Inhibition of poly(ADP-ribose) polymerase (PARP) by a novel, potent inhibitor, INO-1001, was examined in two rodent and one human fibroblast cell lines, after single and fractionated radiation treatments. Since PARP plays a role in the early events following DNA damage and influences the effectiveness of DNA repair, its inhibition has been proposed to constitute a drug target for the development of novel radiosensitizers. We found that INO-1001 effectively inhibited PARP activity at non-cytotoxic concentrations. Combination treatment of 10 microM INO-1001 and a single dose of radiation resulted in significant radiosensitization of all three cells lines (enhancement ratios 1.4-1.6). This radioenhancement was even greater when the drug and radiation were given as fractionated treatments (enhancement ratio 8.0). Apoptosis (as evaluated by TUNEL staining) was not enhanced by the treatments, suggesting that inhibiting PARP enzyme activity by INO-1001 enhanced radiation-induced cell killing by interfering with DNA repair mechanisms, resulting in necrotic cell death. INO-1001 therefore, appears to have potential as a potent enhancer of radiation sensitivity, without any intrinsic cytotoxicity from the drug alone.

Animals↗

PubMed2004

Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy.

PURPOSE: To present an overview of the significance of erbB tyrosine kinase family members as prognostic-predictive factors and as targets of therapeutic intervention in patients with head-and-neck carcinomas (HNCs). METHODS AND MATERIALS: The data of clinical studies addressing the correlation between the expression of erbB family tyrosine kinases, particularly epidermal growth factor receptor (EGFR), and the prognosis and pattern of failure were reviewed, along with the response of HNCs to EGFR antagonists such as a chimeric monoclonal antibody and a couple of small molecule tyrosine kinase inhibitors. RESULTS: Correlative biomarker studies showed that most HNCs express high levels of EGFR and/or other members of the erbB family. Several studies have demonstrated that patients with EGFR-overexpressing tumors had significantly worse overall survival. Compelling evidence has emerged showing that EGFR-overexpressing HNCs respond more poorly to radiotherapy (RT), although data of its impact on the response to chemotherapy are scarce. Clinical studies have so far showed that tyrosine kinase inhibitors have rather limited antitumor activities when given alone. Stimulated by promising preclinical data, the value of EGFR antagonists in the combined modality setting, particularly with RT, is being addressed in clinical trials. CONCLUSION: Members of the erbB receptor tyrosine kinase family, particularly EGFR, were found to be a strong biomarker for poor prognosis and HNC resistance to RT. The available data showed that EGFR antagonists given as single modality therapies yield rather limited antitumor activity. The results of trials testing the efficacy of combining EGFR antagonist with RT or chemotherapy will emerge within the next few years.

Antibodies, Monoclonal↗

PubMed2004

Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies.

PURPOSE: Evidence is rapidly mounting that dysregulated epidermal growth factor receptor (EGFR) signaling is one of the underlying mechanisms of more aggressive tumor behavior and increased tumor resistance to cytotoxic agents, including radiotherapy (RT). This has led to extensive preclinical and clinical studies aimed at developing effective treatment strategies that counteract EGFR-mediated signaling. In this article, we review preclinical studies, primarily from our laboratory, addressing the role of EGFR in tumor radioresponse and the use of C225, a human-mouse chimeric anti-EGFR monoclonal antibody, to improve the results of RT. METHODS AND MATERIALS: Mouse carcinomas were used to study the influence of EGFR on tumor radioresponse. EGFR expression was assessed by Western blot analysis, and cDNA transfection experiments were performed to determine a causal relationship between EGFR and tumor cell radioresistance. A431 human tumor xenografts growing in nude mice were used to test whether blockade of EGFR with C225 anti-EGFR antibody enhances tumor radioresponse. RESULTS: Our studies showed that high levels of EGFR were associated with decreased tumor radiocurability of murine carcinomas. The causal role of EGFR in mediating cellular resistance to RT was demonstrated by transfecting the EGFR cDNA into the cells with low levels of EGFR. The EGFR-high expression-transfected clones became more resistant to RT. RT activated EGFR and its downstream signaling pathways in radioresistant, but not in radiosensitive, tumors, which can be regarded as an adaptive response to radiation damage. Additional studies investigated whether blockade of EGFR and inhibition of EGFR-mediated downstream signaling can be exploited for therapeutic purposes. The results described here showed that treatment of human tumor xenografts with C225 can markedly enhance the tumor response to RT, as assessed by both tumor growth delay and the tumor cure rate. CONCLUSION: The findings from our in vivo preclinical studies suggest that overexpression of EGFR could serve as a predictor of tumor treatment outcome by RT and as a therapeutic target to enhance the efficacy of RT. This therapeutic strategy is currently being explored in patients with head-and-neck cancers.

Animals↗

PubMed2004

Predicting radiosensitivity using DNA end-binding complex analysis.

Previous reports have suggested that measuring radiosensitivity of normal and tumor cells would have significant clinical relevance for the practice of radiation oncology. We hypothesized that radiosensitivity might be predicted by analyzing DNA end-binding complexes (DNA-EBCs), which form at DNA double-strand breaks, the most important cytotoxic lesion caused by radiation. To test this hypothesis, the DNA-EBC pattern of 21 primary human fibroblast cultures and 15 tumor cell lines were studied. DNA-EBC patterns were determined using a modified electrophoretic mobility shift assay and were correlated with radiosensitivity, as measured by SF2. DNA-EBC analysis identified a rapidly migrating ATM-containing band (identified as "band-A") of which the density correlated with SF2 (0.02 </= SF2 </= 0.41) in primary fibroblasts (r(2) = 0.77). The DNA-EBC pattern of peripheral blood lymphocytes was identical to that of fibroblasts. In addition, band-A density correlated with SF2 (0.35 </= SF2 </= 0.80) in 15 human tumor cell lines (r(2) = 0.91). Densitometry of other bands, or total DNA-EBC binding, correlated more poorly with SF2 (r(2) < 0.45). These data indicate that DNA-EBC analysis may be a practical, clinically relevant predictor of tumor and primary cell radiosensitivity.

Cell Line↗

PubMed2004

Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors.

Cyclooxygenase-2 (COX-2) is an enzyme expressed primarily in pathologic states, such as inflammatory disorders and cancer, where it mediates prostaglandin production. Its overexpression is associated with more aggressive biologic tumor behavior and adverse patient outcome. Increasing evidence shows that agents that selectively inhibit COX-2 enhance tumor response to radiation or chemotherapeutic agents. This article gives an overview of some of this evidence. In addition, we describe new results showing that celecoxib, a selective COX-2 inhibitor, enhanced response of A431 human tumor xenografts in nude mice to radiation by an enhancement factor (EF) of 1.43 and to the chemotherapeutic agent docetaxel by an EF of 2.07. Celecoxib also enhanced tumor response when added to the combined docetaxel plus radiation treatment (EF = 2.13). Further experiments showed that selective COX-2 inhibitors enhanced tumor cell sensitivity to ionizing radiation, involving inhibition of cellular repair from radiation damage and cell cycle redistribution as mechanisms for some cell types. The results show that selective COX-2 inhibitors have the potential to improve tumor radiotherapy or radiochemotherapy, and this therapeutic strategy is currently under clinical testing.

Animals↗

PubMed2004

Improvement strategies for molecular targeting: Cyclooxygenase-2 inhibitors as radiosensitizers for non-small cell lung cancer.

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory processes and cancer. The enzyme is often overexpressed in premalignant lesions and various cancers, including cancer of the lung. Inhibition of this enzyme with selective COX-2 inhibitors was found to enhance tumor response to radiation in preclinical studies, suggesting that these agents can improve the response of various cancers to radiotherapy. On the basis of these preclinical findings, we initiated clinical trials of the combination of celecoxib, a selective COX-2 inhibitor, with radiotherapy in patients with lung cancer. Here we discuss the rationale for using selective COX-2 inhibitors and describe current clinical protocols and the initial findings.

Carcinoma, Non-Small-Cell Lung↗

PubMed2004

Targeted therapies and radiation for the treatment of head and neck cancer: are we making progress?

Targeting specific biological pathways in tumor development has been heralded as a promising approach to the treatment of cancer. Familiar to most investigators are the studies done with epidermal growth factor receptor (EGFR) antagonists, but newer agents currently under development also target angiogenic or cell cycle pathways. EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Because EGFR overexpression portends for a worse outcome in patients with advanced head and neck cancer (HNC), selective targeting of this signaling pathway has gained attention. The agents selected for initial studies include monoclonal antibodies and tyrosine kinase inhibitors against EGFR. Encouraging laboratory findings in different xenografts resulted in rapid translation into the clinic. Results from initial clinical trials show rather surprisingly that only a minority of patients benefited from EGFR inhibition as monotherapy or in combination with chemotherapy. Current challenges for investigators are to determine (1). who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2). how to sequence these agents with radiation and/or cytotoxic compounds, (3). reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4). mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multiple targeted therapy. Well-integrated laboratory-clinical research programs are needed to address these issues.

Combined Modality Therapy↗

PubMed2004

COX-2 and its inhibition as a molecular target in the prevention and treatment of lung cancer.

Lung cancer is the leading cause of cancer death in the USA. Conventional therapy using chemotherapy, radiation therapy, and a combination of the two, has yielded modest improvement in patient outcome. Dysfunction and dysregulation of many molecular processes and signaling pathways are involved in the development and growth of malignant lung tumors, and in conferring resistance to standard cancer treatments. Cyclooxygenase (COX)-2, an enzyme involved in prostaglandin production in pathologic states, is often overexpressed in premalignant and malignant lesions. Overexpression of COX-2 in lung cancer is associated with more aggressive biologic tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings quickly led to clinical studies. Phase I and II clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, and the rationale for using selective COX-2 inhibitors combined with radiotherapy and chemotherapy, will be described. Current clinical protocols and preliminary findings will also be summarized.

Clinical Trials as Topic↗

PubMed2004

Epidermal growth factor receptor as a target to improve treatment of lung cancer.

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.

Antineoplastic Agents↗

PubMed2003

Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?

Results of preclinical studies suggesting that the efficacy of molecular therapies is enhanced when they are combined with radiation have generated a surge of clinical trials combining these modalities. We reviewed the literature to identify the rationale and experimental foundation supporting the use of cyclooxygenase-2 (COX-2) inhibitors with standard radiotherapy regimens in current clinical trials. Radiation affects the ability of cells to divide and proliferate and induces the expression of genes involved in signaling pathways that promote cell survival or trigger cell death. Future advances in radiotherapy will hinge on understanding mechanisms by which radiation-induced transcription of genes governs cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. COX-2 is expressed in all stages of cancer, and in several cancers its overexpression is associated with poor prognosis. Evidence from clinical and preclinical studies indicates that COX-2-derived prostaglandins participate in carcinogenesis, inflammation, immune response suppression, apoptosis inhibition, angiogenesis, and tumor cell invasion and metastasis. Clinical trial results have demonstrated that selective inhibition of COX-2 can alter the development and the progression of cancer. In animal models, selective inhibition of COX-2 activity is associated with the enhanced radiation sensitivity of tumors without appreciably increasing the effects of radiation on normal tissue, and preclinical evidence suggests that the principal mechanism of radiation potentiation through selective COX-2 inhibition is the direct increase in cellular radiation sensitivity and the direct inhibition of tumor neovascularization. Results of current early-phase studies of non-small-cell lung, esophageal, cervical, and brain cancers will determine whether therapies that combine COX-2 inhibitors and radiation will enter randomized clinical trials.

Animals↗

PubMed2003

The epidermal growth factor receptor mediates radioresistance.

PURPOSE: The epidermal growth factor (EGF) receptor is frequently overexpressed in malignant tumors, and its level is correlated with increased cellular resistance to ionizing radiation. However, no precedent studies have investigated whether expression of EGF receptor would by itself confer on cancer cells resistance to radiation. The current study is aimed to address this question. METHODS AND MATERIALS: A full-length human EGF receptor expression vector was transfected into the OCA-I murine ovarian carcinoma cells for stable clones expressing various levels of EGF receptors. Apoptosis and cell clonogenic survival assays were used to evaluate the sensitivity of the resulting cell clones to ionizing radiation. RESULTS: OCA-I cell clones expressing various levels of EGF receptor (OCA-I EGFR) were obtained. These clones showed an EGF receptor level-dependent increase in resistance to ionizing radiation, measured by apoptosis and cell clonogenic survival assays. Compared with the results for parental OCA-I and control vector-transfected OCA-I cells at the 10% cell survival level, the radioresistance was increased by a factor of 1.60 for EGFR-C5 (high level of EGF receptor expression), 1.37 for EGFR-C3 (intermediate level of EGF receptor expression), and 1.28 for EGFR-C1 (low level of EGF receptor expression). Treatment of the OCA-I EGF receptor transfectants with the anti-EGF receptor monoclonal antibody C225 downregulated the levels of EGF receptor, reduced the phosphorylation levels of EGF receptor downstream substrates (such as Akt and MAPK), and reversed the cellular radioresistance. CONCLUSION: Our results demonstrate that overexpression of the EGF receptor conferred cellular resistance to ionizing radiation. The EGF receptor is thus a valid target for potential radiosensitization.

Animals↗

PubMed2003

Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells.

Flavopiridol, a cyclin-dependent kinase (cdk) inhibitor, can cause cell cycle arrest, induce apoptosis in cancer cells, and inhibit tumor cell growth in vivo. The present study investigated the in vitro radiosensitizing effect of flavopiridol and the underlying molecular mechanisms in a murine ovarian cancer cell line, OCA-I. Flavopiridol inhibited cell growth in a dose-dependent manner and enhanced cell radiosensitivity assessed by the clonogenic cell survival assay. A flavopiridol dose of 300 nM, given for 1 day, enhanced radiosensitivity by a factor of 2.1. Clonogenic cell survival after split-dose radiation showed that flavopiridol inhibited repair from radiation damage. In addition, flavopiridol treatment (300 nM, 1 day) resulted in decreased levels of Ku70 and Ku86 proteins that play a role in DNA repair processes, suggesting that DNA repair processes may have been disrupted by this agent. Flow cytometry analysis showed that flavopiridol (300 nM, 1 day) accumulated the cells in G(1) and G(2) phases, with a significant reduction in the S phase component. This cell cycle redistribution is likely another mechanism underlying flavopiridol-induced cell radiosensitivity. Flavopiridol down-regulated cyclin D1 and cyclin E protein levels and also inhibited phosphorylation of retinoblastoma protein, which is inconsistent with the observed cell cycle arrest. Among the cdks tested, cdk-9, the catalytic subunit of positive transcription elongation factor b, was significantly down-regulated by flavopiridol, suggesting that flavopiridol may modulate cellular transcription processes. Furthermore, flavopiridol on its own induced apoptosis in the OCA-I cells, whereas in combination with radiation, exerted no additional increase in apoptosis. Taken together, our data show that flavopiridol strongly augmented the response of ovarian carcinoma cells to radiation and that the underlying mechanisms included inhibition of sublethal DNA damage repair and cell cycle redistribution. At the molecular level, transcriptional regulation by flavopiridol may have been involved.

Animals↗

PubMed2003

Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability.

PURPOSE: Conjugating drugs with polymeric carriers is one way to improve selective delivery to tumors. Poly (L-glutamic acid)-paclitaxel (PG-TXL) is one such conjugate. Compared with paclitaxel, its uptake, tumor retention, and antitumor efficacy are increased. Initial studies showed that PG-TXL given 24 h before or after radiotherapy enhanced tumor growth delay significantly more than paclitaxel. To determine if PG-TXL-induced enhancement is obtained in a more clinically relevant setting, we investigated PG-TXL effects on tumor cure. METHODS AND MATERIALS: Mice bearing 7-mm-diameter ovarian carcinomas were treated with PG-TXL at an equivalent paclitaxel dose of 80 mg/kg, single dose or 5 daily fractions of radiation or both PG-TXL and radiation. Treatment endpoint was TCD(50) (radiation dose yielding tumor control in 50% of mice). Acute radioresponse of jejunum, skin, and hair was determined for all treatments. RESULTS: PG-TXL dramatically improved tumor radioresponse, reducing TCD(50) of single-dose irradiation from 53.9 (52.2-55.5) Gy to 7.5 (4.5-10.7) Gy, an enhancement factor (EF) of 7.2. The drug improved the efficacy of fractionated irradiation even more, reducing the TCD(50) of 66.6 (62.8-90.4) Gy total fractionated dose to only 7.9 (4.3-11.5) Gy, for an EF of 8.4. PG-TXL did not affect normal tissue radioresponse resulting from either single or fractionated irradiation. CONCLUSION: PG-TXL dramatically potentiated tumor radiocurability after single-dose or fractionated irradiation without affecting acute normal tissue injury. To our knowledge, PG-TXL increased the therapeutic ratio of radiotherapy more than that previously reported for other taxanes, thus, PG-TXL has a high potential to improve clinical radiotherapy.

Adenocarcinoma↗

PubMed2003

Chemoradiotherapy: emerging treatment improvement strategies.

BACKGROUND: The use of chemotherapeutic drugs in combination with radiotherapy has become a common strategy for the treatment of advanced cancer. Solid evidence exists showing that chemotherapy administered during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites, including head and neck cancer. These therapy improvements, however, have been achieved at the expense of considerable toxicity, which underscores the need for further improvements. METHODS: The current status of chemoradiotherapy clinical trials for head and neck cancer and research on the emerging treatment improvements were reviewed. A review of potential treatment improvement strategies focused on preclinical investigations on newer chemotherapeutic agents, notably taxanes and nucleoside analogues, as well as on molecular targets such as epidermal growth factor receptor (EGFR) or cyclooxygenase-2 (COX-2) enzyme. RESULTS: Concurrent, but not induction (drugs given before radiotherapy), chemoradiotherapy improves locoregional tumor control and survival benefit in head and neck carcinoma relative to radiotherapy alone. In comparison, both concurrent and induction chemoradiotherapy showed therapeutic advantage over radiotherapy alone in the treatment of lung cancer. These therapeutic improvements were achieved with standard chemotherapeutic drugs, most commonly cisplatin-based chemotherapy. Biologically, chemotherapy interacts with radiation through a number of mechanisms, including inhibition of cellular repair, cell cycle effects, and inhibition of tumor cell regeneration. Potential avenues emerged to further improve chemoradiotherapy. One of these involves the newer chemotherapeutic agents, taxanes and nucleoside analogues, which in preclinical studies exhibited strong tumor radiosensitization and therapeutic gain. The clinical benefit of these agents is currently under testing. Another approach for improvement of chemoradiotherapy consists of inhibiting molecules selectively or preferentially expressed on tumor cells, such as EGFR and COX-2, both shown to render cellular resistance to drugs or radiation. Agents that selectively inhibit these molecules are becoming available at a rapid rate, and many of them have been shown in preclinical testing to be highly effective in improving tumor radioresponse or chemoresponse without affecting normal tissues. CONCLUSIONS: Concurrent chemoradiotherapy, using standard chemotherapeutic agents, has emerged as an effective treatment for advanced cancer, but unfortunately at the expense of considerable increase in normal tissue toxicity. There are a number of potential emerging treatment strategies to further improve chemoradiotherapy. One consists of using newer chemotherapeutic drugs, which in preclinical studies are potent enhancers of tumor radioresponse. Another approach consists of targeting EGFR or COX-2 with selective inhibitors of these molecules.

Combined Modality Therapy↗