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Biomedical subjects

H Choy

Publications and source records attributed to H Choy.

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

Preclinical evaluation of the orally active camptothecin analog, RFS-2000 (9-nitro-20(S)-camptothecin) as a radiation enhancer.

PURPOSE: To test for enhancement of radiation effects in vitro and in vivo by the orally administered camptothecin derivative, 9-nitrocamptothecin (RFS-2000); to study whether the mechanism of this enhancement involves inhibition of sublethal damage recovery. METHODS AND MATERIALS: In vitro: H460 human lung carcinoma cells were incubated with RFS-2000 for various times at 37 degrees C, irradiated, immediately rinsed, and assessed for colony-forming ability. Sublethal damage recovery (SLDR) was also assessed using two split doses of radiation. In vivo: H460 cell xenografts were used in nude mice. Tumors were grown subcutaneously on the flank, then treated with RFS-2000 (1 mg/kg) and/or radiation (2 Gy) for 5 consecutive days. Tumor growth delay was then measured for each treatment group. RESULTS: Radiation enhancement was observed in vitro for incubation times between 4 and 24 hr with 10 nM RFS-2000. Using a 24-hr treatment, the radiation dose enhancement ratio values (DER) for 5, 10, and 15 nM were 1.22, 1.54, and 2.0, respectively. Incubation with 10 nM RFS-2000 inhibited SLDR by a factor of 2. The results of three independent in vivo experiments showed that RFS-2000 can enhance the effects of fractionated radiotherapy, with an enhancement factor (EF) of 1.64. CONCLUSION: Our results show that RFS-2000 can enhance the effects of radiation in human lung cancer cells both in vitro and in vivo, and that the mechanism of this effect may involve the inhibition of SLDR.

Administration, Oral↗
PubMed2000

Patterns of practice survey for nonsmall cell lung carcinoma in the U.S.

BACKGROUND: Nonsmall cell lung carcinoma comprises approximately 75% of all lung carcinoma cases in the U.S. Newly evolving strategies have created considerable controversy regarding the optimal treatment for patients diagnosed with this disease. METHODS: A 17-item survey was designed to collect demographic data and information regarding practice patterns for nonsmall cell lung carcinoma, including patient assessment, treatment approaches, and roles of chemotherapy and radiotherapy. Surveys were mailed in the summer of 1997 to approximately 9200 oncologists of all types throughout the U.S. Practice settings included private office, private hospital, academic, university-affiliated office, government, and Veterans Administration institutions. RESULTS: Approximately 10% of the oncologists responded (n = 979), including 499 medical oncologists (51%), 464 radiation oncologists (47%), and 16 others (2%). For the adjuvant treatment of surgically resected N1-2 disease, combined modality treatment was preferred over radiation therapy alone by medical oncologists (48% vs. 16%; P<0.001) and radiation therapy alone was preferred over combined modality treatment by radiation oncologists (55% vs. 38%; P<0.001). The combination of paclitaxel and carboplatin was the preferred first-line regimen for all stages of nonsmall cell lung carcinoma by the majority of medical oncologists (55%), whereas the majority of radiation oncologists (58%) chose the combination of etoposide and platinum. With regard to the optimal combined modality approach, respondents were divided evenly between concurrent chemoradiotherapy (34%) and sequential chemoradiotherapy (31%). Overall, respondents reported basing treatment decisions largely on published literature (55%) compared with personal experience (19%), seminars and colleagues (16%), and clinical trial availability (10%) (P<0.001). CONCLUSIONS: This survey confirms many differences in practice patterns among medical oncologists and radiation oncologists in the treatment of patients with nonsmall cell lung carcinoma and suggests the need for the multidisciplinary management of this entity. In addition, the current study demonstrates that reliance on the medical literature as a basis for treatment steadily declines the longer the physician has been in practice.

Analysis of Variance↗
PubMed2000

Combined effects of the orally active cisplatin analog, JM216, and radiation in antitumor therapy.

PURPOSE: We evaluated the orally administered platinum agent, JM216, in combination with ionizing radiation both in vivo and in vitro against human tumor cells. METHODS: H460 human lung carcinoma cells were used as a subcutaneous xenograft in nude mice. JM216 (30 mg/kg) was administered orally, and radiation treatments (2 Gy) were given 1 h after JM216 delivery for five consecutive days. For in vitro analysis, attached H460 cells were treated with JM216 (15 microM) for 1 h and then irradiated. Cells were rinsed 20 min later, and survival was determined by clonogenic assay. RESULTS: Tumor growth delay measurements showed that the combination of JM216 and radiation was additive in vivo, with an enhancement ratio of 1.24. In vitro clonogenic survival experiments demonstrated a dose enhancement ratio of 1.23. Isobologram analysis showed that this interaction was also additive. CONCLUSIONS: These data demonstrate that the combination of JM216 and fractionated radiotherapy is more effective against human lung cancer xenografts than either agent alone, and the in vivo results were supported by those observed using an in vitro system with the same tumor cell line.

Animals↗
PubMed2000

Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol.

2-Methoxyestradiol. 2-Methoxyestradiol (2-ME) is an endogenous estradiol metabolite that disrupts microtubule function, suppresses murine tumors, and inhibits angiogenesis. Since some microtubule inhibitors have been shown to alter radiosensitivity, we have evaluated 2-ME as a radiation enhancer in vitro. H460 human lung cancer cells were plated, treated with 2-ME for 24 h, and irradiated; then colony-forming ability was assessed. The radiation dose enhancement ratios (DERs) using this protocol were 1.3, 1.8 and 2.1 for 1, 1.5 and 2 microM 2-ME, respectively. Using a single-cell plating protocol, the respective DERs were 1.2, 1.5 and 1.8. The parent compound of 2-ME, beta-estradiol, did not enhance radiation effects at equally cytotoxic doses. Isobologram analysis showed that 1 microM 2-ME was additive with radiation, but that 1.5 and 2 microM were synergistic. Cell cycle analysis showed a dose-dependent increase in the percentage of cells in the radiosensitive G(2)/M phase after a 24-h treatment with 2-ME; a threefold increase in the percentage of cells in G(2)/M phase was observed using 2 microM 2-ME. Treatment with 2 microM 2-ME almost completely inhibited repair of sublethal damage (SLD) as shown using split-dose recovery. Radiosensitive, repair-deficient murine SCID (severe combined immunodeficient) cells did not show enhancement of radiation effects with 2 microM 2-ME, but enhancement was observed in the wild-type parental cells (CB-17). SCID cells complemented with human DNA-dependent protein kinase restored radioenhancement by 2-ME. In addition, MCF-7 breast cancer cells were also radiosensitized by 2 microM 2-ME (DER = 2.1). These data suggest that 2-ME is a potential radiation sensitizer, in addition to its previously reported antitumor and antiangiogenic properties. We have verified the antiangiogenic activity of 2-ME in vitro using human endothelial cells. Based on these results, we hypothesize that the mechanism of radiation enhancement may involve redistribution of cells into G(2)/M phase by 2-ME, and that the resulting population of cells is repair-deficient and thus radiosensitive.

2-Methoxyestradiol↗
PubMed2000

A phase I trial of outpatient weekly irinotecan/carboplatin and concurrent radiation for stage III unresectable non small-cell lung cancer: a Vanderbilt-Ingram Cancer Center Affiliate Network Trial.

Irinotecan (CPT-11), a topoisomerase I inhibitor, has been shown in preclinical studies to be a potent radiosensitizer. Carboplatin, a known radiosensitizer with single-agent activity in non small-cell lung cancer (NSCLC), is felt to be a rational choice in combination with irinotecan. We have completed the initial portion of a phase I study, in patients with locally unresectable lung cancer, combining irinotecan with thoracic radiation. Thirteen patients have been entered onto this study through three dose levels (30 to 50 mg/m2/week) of irinotecan. There were seven partial responses in 12 evaluable patients, for an over-all response rate of 58%. Nausea, vomiting, and esophagitis were the principal toxicities of weekly irinotecan and concurrent thoracic radiation. As the maximum tolerated dose (MTD) of irinotecan with radiation has been established at 40 mg/m2/week, we are currently accruing patients to the second phase of this study with the addition of carboplatin (AUC = 2). Thus far toxicity has primarily been esophagitis.

Journal Article↗
PubMed2000

A phase I trial of outpatient weekly docetaxel and concurrent radiation therapy for stage III unresectable non small-cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) Trial.

Docetaxel has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its role as a cell cycle synchronizer for the G2/M radiosensitive phase of the cell cycle. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of docetaxel with concurrent thoracic radiation therapy (TRT) to patients with unresectable stage III non small-cell lung cancer (NSCLC). Fifteen patients were entered into this study. Docetaxel was administered as a 1-hour intravenous (I.V.) infusion, repeated every week for 6 weeks with starting dose of 20 mg/m2. Doses were escalated in 10 mg/m2 increments in successive cohorts of three new patients, if tolerated. Unacceptable toxicity was defined as grade = 3 nonhematologic or hematologic toxicity according to Eastern Cooperative Oncology Group (ECOG) toxicity criteria. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). At the first dose level (20 mg/m2/week), one patient developed grade 4 hyperglycemia and accrual was expanded to five patients. At the second level (30 mg/m2/week), two out of six patients developed grade 3 esophagitis. At the third level (40 mg/m2/week), two out of four patients developed grade 3 esophagitis and one patient developed grade 3 pulmonary toxicity. The weekly docetaxel MTD with concurrent radiation therapy (RT) was found to be 30 mg/m2. The DLT was esophagitis and pulmonary toxicity. Other toxicities encountered included skin reaction, nausea and vomiting, as well as diarrhea. Additionally, there were no treatment-related mortalities or late-occurring toxicities. Esophagitis was the principal DLT of concurrent weekly docetaxel and thoracic radiation in the outpatient setting. The MTD of concurrent weekly docetaxel with TRT is 30 mg/m2 weekly for 6 weeks. This study is still open to accrual with weekly docetaxel and TRT in locally advanced NSCLC patients.

Journal Article↗
PubMed2000

Combination chemoradiotherapy with gemcitabine: potential applications.

Gemcitabine (Gemzar) is a novel deoxycitidine drug that has demonstrated promising single-agent activity in non-small-cell lung cancer and has been proven to be a potent radiosensitizer. Although the exact mechanism of the radiosensitizing effect is unknown, several studies have focused on the drug's effect on deoxyadenosine triphosphate (dATP) pool depletion or cell-cycle manipulation. A number of trials have evaluated this feature of gemcitabine by combining chemotherapy and radiation in various doses and schedules, and those studies are described in this article. Gemcitabine appears to be a promising agent to be combined with radiation therapy. However, further clinical trials are needed to define optimal doses, toxicity, and efficacy.

Agranulocytosis↗
PubMed2000

Weekly irinotecan and concurrent radiation therapy for stage III unresectable NSCLC.

In preclinical studies, the topoisomerase I inhibitor irinotecan (Camptosar, CPT-11) has demonstrated activity as a radiosensitizer, probably due to its ability to inhibit potentially lethal radiation damage repair. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly irinotecan with concurrent thoracic radiation therapy for patients with unresectable stage III non-small-cell lung cancer. For this study, 13 patients received three dose escalations (from 30 to 40 to 50 mg/m2/wk). At the first dose level, one patient developed grade 5 esophagitis. Accrual was expanded to seven patients. None of the remaining six patients developed esophagitis. At the second dose level (40 mg/m2/wk), the worst toxicity, which developed in one patient, was grade 2 esophagitis. At the third dose level (50 mg/m2/wk), two of three patients developed grade 4 nausea and vomiting; grade 3 or 4 esophagitis also occurred in two patients. Of the 12 evaluable patients, seven achieved a partial response, for an overall response rate of 58%. In conclusion, nausea, vomiting, and esophagitis appear to be the principal DLTs of concurrent weekly irinotecan and thoracic radiation in the outpatient setting. The MTD of concurrent weekly irinotecan with thoracic radiation therapy appears to be 40 mg/m2 weekly for 6 weeks. To confirm the MTD of this combination, this study is still open to accrual at the second dose level (40 mg/m2) in combination with carboplatin.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition.

PURPOSE: To test for in vitro radiopotentiation by the orally-administered platinum (IV) complex, JM216; to compare these results to cisplatin and carboplatin; and to investigate whether the mechanism of radiopotentiation involves repair inhibition of radiation-induced DNA damage. METHODS AND MATERIALS: H460 human lung carcinoma cells were incubated with the drugs for 1 h at 37 degrees C, irradiated at room temperature, and returned to 37 degrees C for 20 min. Cells were then rinsed and colony forming ability was assessed. Wild-type V79 Chinese hamster cells and radiosensitive, DNA repair-deficient mutant cells (XR-V15B) were also studied along with H460 cells. Ku86 cDNA, which encodes part of a protein involved in DNA repair, was transfected into XR-V15B cells as previously described. The effect of JM216 on sublethal damage repair (SLDR) was also assessed using split-dose recovery. RESULTS: Using equally cytotoxic doses of JM216, cisplatin, and carboplatin, the radiation dose enhancement ratios (DER) were 1.39, 1.31, and 1.20, respectively; the DER with 20 microM JM216 was 1.57. JM216 (20 microM) did not significantly change the final slope of radiation survival curves, but greatly reduced the survival curve shoulder. V79 cells also showed radioenhancement using 20 microM JM216, but no enhancement occurred using XR-V15B cells. Transfection of Ku86 cDNA into XR-V15B cells restored radiopotentiation by JM216 to wild-type V79 levels. In addition, 20 microM JM216 completely inhibited sublethal damage repair in H460 cells. CONCLUSION: Our results show that JM216 can potentiate the effects of radiation in human lung cancer cells, and that the mechanism of this effect is probably inhibition of DNA repair by JM216.

Administration, Oral↗
PubMed1999

National survey on prophylactic cranial irradiation: differences in practice patterns between medical and radiation oncologists.

PURPOSE: Prophylactic cranial irradiation (PCI) in the treatment of small cell lung cancer (SCLC) patients remains controversial in the oncology community because of its potential for long-term toxicity and unproven survival benefit in randomized trials. A national survey of 9176 oncologists was conducted to characterize the use of PCI with regard to physician demographics, patient characteristics, and oncologists' beliefs. METHODS: Data was collected via a questionnaire letter survey. Biographical data, treatment patterns, and clinical impressions were analyzed by the generalized linear model and generalized estimating equations method. RESULTS: There were 1231 responders overall (13.4% of those surveyed), including 628 (51%) radiation oncologists (RO), 587 (48%) medical oncologists (MO), 8 (0.6%) surgical oncologists, and 8 (0.6%) from other oncology subspecialties. Of respondents, 74% overall recommend PCI in limited-stage patients, including 65% of MO and 82% RO (p = 0.001). Of responders who recommend PCI in limited-stage patients, 67% do so only after complete response to initial therapy. Only 30% of respondents recommend PCI for extensive-stage SCLC patients (p = 0.001), and 94% of these recommend PCI only when those patients have a complete response after initial therapy. Interestingly, 38% of responding MO feel that PCI improves survival of limited-stage patients, but only 11% believe PCI improves quality of life. Of the RO, 48% believe PCI improves survival in limited-stage SCLC, and 36% feel PCI improves quality of life (p < 0.05 and p < 0.01, respectively). MO responders believe PCI causes late neurological sequelae more often than do RO responders (95% vs. 84%, p < 0.05), with impaired memory (37%), chronic fatigue (19%), and loss of motivation (13%) as most commonly seen side effects. Only 1.5% overall, however, routinely obtain neuropsychiatric testing in PCI patients, and 42% overall never obtain them. CONCLUSION: Results confirm that oncologic subspecialists have statistically significant differences in opinion regarding the use of PCI. However, these differences may not translate into large differences in clinical practice. Most oncologists continue to recommend PCI in limited-stage SCLC patients, despite many believing PCI may not provide a survival advantage nor improve quality of life.

Brain Neoplasms↗
PubMed1999

Enhancement of radiation effects by combined docetaxel and carboplatin treatment in vitro.

This study was designed to evaluate the combination of docetaxel (Taxotere) and carboplatin for radiopotentiation in vitro. H460 human lung carcinoma cells were treated with docetaxel (or paclitaxel) for 1 h and rinsed. After 24 h, the cells were treated with carboplatin for 1 h, irradiated, and colony forming ability was assesed. Using various doses of docetaxel with 100 microM carboplatin, the dose enhancement ratio (D.E.R.) for drugs only was 1.26. When 25 nM docetaxel was used with various doses of radiation, the radiation D.E.R. was 1.41. With all three agents combined, and after normalization for combined drug effects, the radiation D.E.R. was 1.55. Similar values were obtained using paclitaxel with these agents. Significant redistribution of cells into the radiosensitive G2/M phase was observed using a dose of paclitaxel (750 nM), which also caused radiation enhancement. However, an equally cytotoxic dose of docetaxel (25 nM) did not result in any cell cycle redistribution; this phenomenon was only observed at higher doses. This study shows that the combination of docetaxel and carboplatin enhance the effects of radiation in vitro more effectively than either drug seperately. In addition, our data show that the mechanism of radiopotentiation by docetaxel probably does not involve a G2/M block in H460 cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Concurrent paclitaxel, carboplatin, and radiation therapy for locally advanced non-small cell lung cancer.

Combination chemotherapy plus radiation therapy for non-small cell lung cancer has several theoretical advantages: the potential of chemotherapy to radiosensitize tumors, the possibility of improved local control due to combined treatment, and the opportunity for spatial cooperation, attacking disease both locally and systemically and thus potentially increasing response and, ultimately, survival. The combination of radiotherapy plus standard chemotherapy (etoposide plus cisplatin) has yielded limited success; therefore, new and novel chemotherapies have been sought. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the prototype of a novel class of drugs, the taxanes, has proven feasible both alone and with other agents in combined-modality regimens with radiation. Concurrent paclitaxel/carboplatin/radiotherapy appears to offer a relatively safe and more active regimen to control local and metastatic non-small cell lung cancer than the current standard. This report reviews the range of experience with paclitaxel-based combined-modality therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Concurrent paclitaxel and thoracic irradiation for locally advanced esophageal cancer.

Esophageal cancer is a major cause of morbidity and mortality worldwide. Although patients often present with apparently resectable disease, systemic spread frequently occurs before the development of symptoms and detection of tumor. The use of combined chemoradiation therapy, particularly before resection, appears to prolong survival and increase cure rates in certain histologic subtypes. Four randomized phase III trials compared preoperative chemoradiotherapy plus surgery with surgery alone. In trials including only patients with squamous histology, no improvement in survival was observed with preoperative chemoradiation therapy; however, in a trial including only patients with adenocarcinoma histology, improved median and overall survival were observed. Paclitaxel has been evaluated as a single agent in a phase II trial in previously untreated patients with locally advanced unresectable or metastatic esophageal cancer; the overall response rate was 32% and median survival was 13.2 months. Paclitaxel-based combinations also have been evaluated in esophageal cancer; particularly encouraging preliminary results have been achieved with paclitaxel/cisplatin/5-fluorouracil. Because paclitaxel is a potent radiosensitizer, it also has been evaluated in combination with radiation therapy for esophageal and other thoracic cancers, alone and in combination with other chemotherapeutic agents. Preliminary results suggest that neoadjuvant therapy with paclitaxel-based combinations (including 5-fluorouracil and cisplatin) and radiation is highly active, with variable toxicity. A goal of future trials is to assess paclitaxel-based combined modality therapy in combination with other new chemotherapeutic agents.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Single-agent paclitaxel and radiation for non-small cell lung cancer.

Lung cancer must be viewed as a systemic disease, and control of latent metastases at both regional and systemic sites is the goal of therapy. Combined modalities have emerged as the dominant strategy with which to manage latent metastases, and paclitaxel has several properties, including a modest toxicity profile, significant activity, and radiosensitization potential, which contribute to its effectiveness in this setting. In phase I clinical trials, paclitaxel was administered weekly in combination with radiation therapy (60 Gy) in the outpatient setting to patients with stage III non-small cell lung cancer (NSCLC). The dose-limiting toxicity, which occurred at a paclitaxel dose of 70 mg/m2/wk, was esophagitis; thus, a paclitaxel dose of 60 mg/m2/wk was recommended for phase II evaluation. In the phase II trial in patients with inoperable stage IIIA or stage IIIB NSCLC, paclitaxel 60 mg/m2/wk (for 6 weeks) plus radiation therapy (60 Gy) resulted in an overall response rate of 86%. The overall median survival was 20 months, and projected 1-, 2-, and 3-year survival rates were 60%, 54%, and 39%, respectively. These results demonstrate the feasibility and potential efficacy of this combination in the treatment of regionally advanced malignancies. When paclitaxel is administered using this schedule, it appears to exhibit an altered pattern of toxicity, with much lower incidences of hematologic and neurologic toxicities, which may improve the overall therapeutic index of this combination. Until curative systemic therapy is developed, combined modality approaches offer the greatest potential for long-term control of advanced NSCLC. Based on the observed activity and toxicity profile, concurrent radiation therapy plus paclitaxel offers significant clinical utility for control of both local and distant metastatic disease.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Esophagitis in combined modality therapy for locally advanced non-small cell lung cancer.

Within the last 10 to 15 years, several randomized trials have validated the importance of chemotherapy in the treatment of locally advanced non-small cell lung cancer and have shown that combined modality therapy improves survival compared with radiotherapy alone. Esophagitis appears to be the primary toxicity, with an increased incidence in combined modality trials. Esophagitis is an inflammatory response of the esophageal mucosa. Treatment with chemotherapy or radiotherapy destroys rapidly dividing cells, such as those in the basal epithelial cell layer. Cell death decreases the renewal rate of the basal epithelium, causing mucosal atrophy, ulceration, and initiation of the inflammatory response. Synergy between chemotherapy and radiotherapy may increase the severity and extent of esophagitis observed with combined modality therapy. Based on Radiation Therapy Oncology Group criteria, the incidence of >/=grade 3 esophagitis following radiation therapy alone or combined modality therapy ranges from less than 5% to 53%. Four sequential, multi-institutional phase I or II studies were conducted during the last 5 years to explore the use of paclitaxel in combined modality therapy for patients with non-small cell lung cancer. In the three phase II trials, esophagitis was the main toxicity, with incidences ranging from 17% to 26% using Radiation Therapy Oncology Group criteria. A multivariate analysis identified a statistically significant correlation between esophageal toxicity and both response to therapy and performance status. Other factors, including gender, age, histology, survival, and length of esophagus within the primary and boost radiation field, were not significantly correlated with esophageal toxicity.

Adult↗
PubMed1999

Taxanes in combined-modality therapy for solid tumors.

The taxanes, paclitaxel and docetaxel, are novel antimitotic agents that are under extensive investigation in clinical trials in patients with various solid tumors. The taxanes have demonstrated significant activity against many solid tumors as single agents and in combination with other chemotherapeutic agents. In addition, paclitaxel and docetaxel arrest cells at the G2/M phase of the cell cycle, which is the most radiosensitive phase. Numerous clinical trials have assessed paclitaxel-based chemoradiation therapy in a variety of tumor types, including non-small-cell lung cancer, small-cell lung cancer, head and neck cancers, esophageal cancer, brain tumors, pancreatic and gastric tumors, and locally advanced breast cancer. Fewer clinical trials have assessed docetaxel plus radiation therapy in these tumor types. This review highlights recent clinical trials of the taxanes in combination with radiation therapy for solid tumors.

Animals↗
PubMed1999

DNA topoisomerase I-targeting drugs as radiation sensitizers.

Combination chemoradiation, alone or as an adjuvant to surgery, has been shown to improve treatment outcomes in a number of human malignancies, but may be limited by normal tissue toxicities. A primary challenge in radiation oncology is the development of drugs that can selectively enhance the cytotoxicity of ionizing radiation against tumor cells. Mammalian DNA topoisomerase I is the major cytotoxic target of a number of newly developed anticancer drugs that have shown efficacy against solid tumors, including colon cancer, ovarian cancer, lung cancer, cancer of the head and neck, and pediatric cancers. Topoisomerase I-targeting drugs exert their cytotoxic effect by producing enzyme-mediated DNA damage, rather than by directly inhibiting enzyme catalytic activity. DNA topoisomerase I recently has been established as a biochemical mediator of radiosensitization in cultured mammalian cells by camptothecin derivatives. Interestingly, this sensitization appears to be schedule-dependent, cell cycle phase-specific, cell line-dependent, and not strictly dependent on drug cytotoxicity. Clinical chemoradiation trials using camptothecin derivatives are currently ongoing. Future studies aimed at better understanding the underlying mechanisms of molecular radiosensitization with topoisomerase I-targeting drugs are pivotal to the clinical application of these agents, as well as in guiding the development of more effective radiosensitizers.

Animals↗