Purpose:The purpose of this study was to analyze different mechanisms (cell cycle synchronization, DNA damage, and apoptosis) that might underlie potential synergy between chemotherapy (paclitaxel or doxorubicin) and radioimmunotherapy with a radionuclides. Experimental Design:Three multiple myeloma cell lines (LP1, RMI 8226, and U266) were treated with 213 Bi-radiolabeled B-B4, a monoclonal antibody that recognizes syndecan-1 (CD138) 24 hours after paclitaxel (1nmol/L) or doxorubicin (10 nmol/L) treatment. Cell survival was assessed using a clonogenic survival assay. Cell cycle modifications were assessed by propidium iodide staining and DNA strand breaks by the comet assay. Level of apoptosis was determined by Apo 2.7 staining. Results: Radiation enhancement ratio showed that paclitaxel and doxorubicin were synergistic with a radioimmunotherapy. After a 24-hour incubation, paclitaxel and doxorubicin arrested all cell lines in the G 2 -M phase of the cell cycle. Doxorubicin combined with a radioimmunotherapy increased tail DNA in the RPMI 8226 cell line but not the LP1or U266 cell lines compared with doxorubicin alone or a radioimmunotherapy alone. Neither doxorubicin nor paclitaxel combined with a radioimmunotherapy increased the level of apoptosis induced by either drug alone or a radioimmunotherapy alone. Conclusion: Both cell cycle arrest in the G 2 -M phase and an increase in DNA double-strand breaks could lead to radiosensitization of cells by doxorubicin or paclitaxel, but apoptosis would not be involved in radiosensitization mechanisms.a-Emitting radioisotopes might be more effective for metabolic radiotherapy than other radionuclides because of their high linear energy transfer and short pathways and because they can target radiation to individual cancer cells (1) and micrometastases (2). Early results with a radioimmunotherapy have been encouraging (1). Like other radionuclides, they could be combined with chemotherapeutic drugs as this strategy has a strong biological rationale (3). However, up to now, most studies have considered combining drugs with Xrays or g-rays, and radiosensitizing of cells by paclitaxel to grays or X-rays (4, 5) has been attributed to three mechanisms: interactions with the cell cycle, apoptosis, and tumor hypoxia (6), those of doxorubicin to induction of DNA damage (7,8) and tumor hypoxia (9). Paclitaxel does not induce DNA damage but promotes microtubule polymerization (10). Our preliminary investigations on three myeloma cell lines (LP1, RPMI 8226, and U266) have shown that doxorubicin or paclitaxel combined with a radioimmunotherapy is more effective than drug alone or a radioimmunotherapy alone. In accordance with results obtained with other forms of radiation (6), the effect was stronger when a radioimmunotherapy was given 24 hours after doxorubicin or paclitaxel. Experiments are in progress to formally show synergism between a radioimmunotherapy and these drugs (11).We have investigated several mechanisms that might give rise to synergy between paclitaxel o...

Micro-arrays can efficiently assess early transcriptomic changes during preoperative radiotherapy for rectal cancer, and may help better understand tumor radioresistance.

SummaryThe influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1* A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects ≥ 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19-3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23-0.77), P = 0.03].