摘要:

Viral oncolysis, or virotherapy, is an endeavor to use viruses as therapeutic agents in an effort to exploit their highly evolved qualities of host cell killing and simultaneous multiplication and spread. This review describes the concept of oncolytic adenoviruses, also called conditionally replicative adenoviruses (CRAds), and recent developments—inspired by early clinical results—that aim at the optimization of CRAd efficacy. Molecular strategies applied for the development of oncolytic adenoviruses include (i) the genetic manipulation of the expression and/or function of key regulatory viral proteins in order to restrict viral replication and spread to tumor cells, (ii) the engineering of the adenoviral capsid for efficient and tumor-targeted infection, and (iii) the incorporation of heterologous genes to facilitate combination therapies or tracking of the virus. Initial clinical trials have provided proof-of-concept for adenoviral oncolysis in patients and a favorable safety profile for oncolytic adenoviruses has been demonstrated. In conclusion, adenoviral oncolysis, with its distinct therapeutic mechanism, shows remarkable therapeutic potential. Advanced generations of virotherapeutics are currently in development.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) has been developed as an antitumor somatostatin analog. TT-232 has no growth hormone release inhibitory effect and does not inhibit the secretion of gastric acid. This analog induces apoptosis in and exerts pronounced antiproliferative effects on various human tumors (colon, pancreas, lymphoma, leukemia, melanoma, hepatoma) cell lines. The growth of human xenografts (prostate, breast carcinoma, lymphoma, melanoma) and animal tumors (colon-26, P-388, S-180, B16, MXT) was inhibited by TT-232 (dose range: 30–750 μg/kg/day) in 54–98% of cases. Continuous long-term infusion proved to be the most effective way of administration. TT-232 combined with decarbazine or etoposide treatment enhanced the antitumor activity of these drugs on human melanoma and lymphoma xenografts, respectively. Regarding the mode of action, TT-232 activates cell cycle inhibitors via SSTR receptors, inhibits tyrosine kinases through interfering with the proliferative signaling cascades, and interacts with an intracellular receptor and an enzyme involved in glycolysis causing translocation of this enzyme to the nucleus, thus inducing apoptosis. TT-232 may be a promising candidate in the therapy of human malignancies.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Epidemiological and clinical studies suggesting a significant inverse relationship between intake of dietary selenium and overall cancer risk have led to initiation of a randomized, placebo-controlled, phase III clinical trial testing the safety and efficacy of selenized yeast as a chemopreventive agent for prostate cancer. Participants eligible for the ‘Negative Biopsy Study’, which was initiated in August 1999, are men considered to be at high risk for prostate cancer because of at least one negative sextant prostate biopsy, which was clinically indicated within 1 year of enrollment to the study. After a 30-day run-in period to ensure protocol compliance, participants are randomized to receive either 200 or 400 μg selenized yeast or matched placebo once daily. Primary study endpoints include development of prostate cancer and prostate-specific antigen (PSA) velocity. Secondary biochemical endpoints include change in chromagranin A and alkaline phosphatase. As of 1 June 2003, 514 eligible participants had been enrolled. Randomization schema was effective for selected parameters including age, body mass index, smoking status, baseline PSA and baseline plasma selenium level. Various data, including medical history, family history, and urological symptoms and specimens (including blood and subsequent prostate biopsy samples) had been collected at baseline, and throughout both the intervention and follow-up stages of the protocol. The goal for accrual is 700 evaluable participants.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Impediment of the promotion and progression stages of carcinogenesis of the prostate could have a profound impact on treatment choice and prognosis for prostate cancer. Efficacious chemopreventive agents that elicit their activity by slowing the processes of progression could make watchful waiting a viable alternative for a large population of men or could delay the necessity for surgery, radiation or other more invasive treatment modalities associated with frequent side effects. Reports from the Nutritional Prevention of Cancer (NPC) study reported that dietary supplementation with selenium significantly reduced the risk of developing prostate cancer. These data led to initiation of the Watchful Waiting Study, a phase II, multi-center, randomized, double-blind, placebo-controlled clinical intervention study testing the effects of two doses of selenized yeast on progression of prostate cancer. Participants are men with biopsy-proven prostate cancer who have elected to forgo therapy and be closely followed by ‘watchful waiting’ that includes quarterly prostate-specific antigen (PSA) screening. Subjects are randomized to receive 200 or 800 μg of selenized yeast or matched placebo daily. Endpoints include time to disease progression and PSA velocity. Secondary endpoints include time to initiation of therapy as well as biochemical markers of disease progression including chromagranin A and alkaline phosphatase. Immunohistochemical analyses for indicators of apoptosis, proliferation and differentiation will be performed on baseline and subsequent prostate biopsy specimens. This report summarizes the primary objectives, research methods and the randomized subjects in this important clinical trial.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The synthesis and biological evaluation of a homologous series of conjugates (9–13) of 2,5-diaziridinylbenzoquinone (DZQ) and 9-carbonylacridine, a DNA intercalating moiety, via a polymethylene unit (n=2–6) are described. In addition, the non-acridine compound 14, analogous to compound 12, and the 5-methyl-DZQ derivatized conjugate 15, an analog of compound 10, were also prepared. Through a Comet assay, compounds 9–13 were shown to produce DNA interstrand cross-links at submicromolar concentrations, consistent with K562 leukemia cells accumulating in the G2/M stage in the cell cycle. The cytotoxicity of compounds 9–15 was examined using a MTT assay on several human cancer cell lines, including chronic myeloid leukemia K562, the non-small cell lung cancers H596 and H460, and colon carcinoma cells BE and HT29. H460 and HT29 are rich in DT-diaphorase (DTD), and H596 and BE cells have negligible amounts of functional DTD. Under continuous exposure of drugs, except to the non-aziridine compound 19b, the IC50values of all other compounds were determined to be in the range of 0.3–11.3 nM. Compound 10, which has a propyl linker group, was subjected toin vivostudies. When BDF1 mice with established mouse mammary carcinoma were treated with compound 10 (2 mg/kg at day 1 and 5 mg/kg at day 7), a significant delay (9–10 days) in cancer growth was recorded when compared to untreated controls. Furthermore, administration of compound 10 tonu/nuBDF1 mice bearing human lung cancer H460 xenograft (1.5 mg/kg for 10 for five consecutive days from day 13 and 17) also showed a significant reduction in tumor growth compared to untreated controls. The half-life of compound 10 in the presence of five different peptidases (porcine esterase, carboxypeptidase A, B and Y, and pepsin) was determined to be between 30 and 60 h.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Peptichemio, a mixture of six short oligopeptides all comprising the alkylating amino acidm-L-sarcolysin, has shown clinical activity in several malignancies. Previous studies have suggested that activity mainly resides in one of the peptides, P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester). In the present study thein vitroactivity of P2 was further investigated and compared to melphalan and the novel alkylating dipeptide J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), which is structurally related to P2 and melphalan. Cytotoxic activity was studied using patient tumor cells in a non-clonogenic cytotoxicity assay, whereas cellular response, and kinetics thereof, were studied in the lymphoma cell line U-937 GTB. Cellular metabolism was studied using microphysiometry, kinetic effects on macromolecular synthesis by radiolabeled substrate incorporation and, finally, the microculture kinetic assay of apoptosis was used to monitor morphologic changes following drug exposure. The assays compared P2 favorably with melphalan. Interestingly J1 was even more cytotoxic, and produced more pronounced effects in the kinetic assays for macromolecular synthesis, metabolic activity and apoptosis. The results indicate that the delivery properties of J1 are improved compared to those of melphalan and P2.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The family of BCR/ABL-related fusion tyrosine kinases (FTKs) is reported to participate in drug resistance in leukemogenesis. Our recent studies revealed a novel potential mechanism of resistance inFTK+cells underlined by the stimulation of DNA repair. In this work we examined a role of TEL family fusion oncoproteins in the response to idarubicin. We used murine pro-B lymphoid cell line BaF3, and itsTEL/ABL,TEL/JAK2andTEL/PDGF&bgr;R-transformed clones. The transformed cells, in contrast to their non-transformed counterparts, exhibited resistance to idarubicin in the range 0.01–1 μM. The drug at 0.3 and 1 μM induced DNA damage in the form of strand breaks or/and alkali-labile sites in both transformed and control cells as evaluated by the alkaline Comet assay. The transformed cells removed the damage within 60 min, while the control cells required 120 min to recover. The results obtained suggest that TEL-related FTKs may stimulate the repair of DNA damaged by idarubicin and be relevant to the resistance of the leukemic cells to this drug.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Oxaliplatin (L-OHP) and stealth pegylated liposomal doxorubicin (PLD) have been shown to be active in pre-treated advanced ovarian cancer (PAOC). The aim of this phase I study was to determine the maximum tolerated dose (MTD) of L-OHP, combined with fixed doses of PLD as salvage treatment of PAOC. Twenty patients with recurrent ovarian cancer previously treated with two (30%) or three lines (70%) of chemotherapy were entered into the trial. Patients had a median age of 64 years (52–77) and a median platinum-free interval of 13 months (range 6–35). Patients received a fixed dose of PLD 40 mg/m2, combined with escalating doses of L-OHP from 80 to 130 mg/m2administered in 1 day, every 3 weeks. Dose escalation was interrupted if 30% or more patients of a given cohort (three patients) exhibited dose-limiting toxicity in the first treatment cycle. The MTD of L-OHP was 130 mg/m2as two out of three patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia during the first cycle of treatment. Amongst 20 evaluable patients, we observed an overall response rate of 55% (95% confidence interval 31.5–76.9%). With a median follow-up of 12 months (3.4±19.2), median time to progression was 9.7 months, while median survival was not reached yet. We conclude that a combination of PLD and L-OHP has a manageable toxicity profile, and can be safely administered as outpatient chemotherapy for heavily pre-treated patients with relapsed ovarian cancer. Promising anti-tumor activity was observed.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We recently reported that regular infusions of adenosine 5′-triphosphate (ATP) inhibited loss of body weight and quality of life in patients with non-small cell lung cancer (NSCLC). In the present paper we investigated whether ATP affects tumor growth and survival in the same group of patients. Fifty-eight NSCLC patients (stage IIIB or IV) were randomly assigned to receive either 10 i.v. 30-h ATP infusions every 2–4 weeks over a 24-week period (n = 28) or no ATP (control patients,n = 30). ATP was given for a median of 6.5 infusions. Differences in time to progression and survival between patients in both groups were tested by means of the log-rank test and Cox regression analysis. Forty-nine patients were evaluable for tumor response. None of the evaluable patients showed a complete or partial response. Median time to progression was 3.9 months [95% confidence interval (CI) = 2.3–5.5] in the ATP group compared to 3.0 months (95% CI = 2.4–3.7) in the control group (p = 0.71). Median survival was 5.6 months (95% CI = 1.1–10.1) for the ATP group and 4.7 months (95% CI = 2.6–6.8) for the control group (p = 0.68). ATP treatment was associated with a significant increase in survival in the subgroup of weight-losing patients with stage IIIB NSCLC: in this subgroup, median survival was 9.3 months (95% CI = 2.1–16.5) for ATP-treated patients versus 3.5 months (95% CI = 2.3–4.7) for control patients (between-group difference:p = 0.009). No significant effect of ATP was observed for weight-losing patients with stage IV NSCLC or for weight-stable NSCLC patients. Although ATP as a single therapy does not lead to tumor regression or increased survival in patients with advanced lung cancer, it may prolong survival in weight-losing patients with stage IIIB lung cancer. The latter finding is intriguing, but requires confirmation in larger clinical trials.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Although 5-fluorouracil remains the mainstay of treatment for advanced gastric cancer (AGC), no standard chemotherapy regimen exists. Combinations of irinotecan with folinic acid and infusional 5-fluorouracil (5-FU) (ILF) have shown good efficacy with acceptable toxicity in patients with metastatic colorectal cancer. At present, only sparse data on ILF are available for AGC. Therefore we conducted a prospective study of this combination in 25 consecutive patients with metastatic gastric cancer. Median age was 63 years, 10 had received prior chemotherapy and 13 presented initially with peritoneal carcinosis. Treatment consisted of irinotecan 80 mg/m2, folinic acid 500 mg/m2and infusional 5-FU 2.0 g/m2over 24 h, given weekly for 6 weeks followed by a 1-week rest. Grade 3/4 hematologic toxicity occurred in six patients (anemia = 4, neutropenia = 1 and leukopenia = 1). Non-hematologic toxicity consisted mainly of nausea/vomiting (grade 3/4 in six patients) and diarrhea (grade 3/4 in 10 patients). The overall response rate was 20% for first- and second-line treatment, with two complete and three partial responses. Another nine patients (36%) had stable disease, for a tumor control rate of 56%. Median time to progression was 4 months, median overall survival and survival for patients with tumor control was 7 and 13 months, respectively. We conclude that ILF is a feasible outpatient regimen with manageable toxicity that provides tumor control in a high proportion of patients with advanced gastric cancer, even among those with unfavorable prognostic features.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID