Continuing the fight against advanced colorectal cancer: new and future treatment options.
Chemotherapy and Gastroenterology Unit, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium.
The benefit of chemotherapy in the treatment of advanced colorectal cancer has now been clearly demonstrated with several studies reporting advantages in terms of overall survival, quality of life and effective palliation following chemotherapy plus supportive care in comparison to supportive care alone. However, the survival benefit achieved with the current 5-fluorouracil (5-FU)-based regimens is modest and thus investigations are ongoing to identify more effective agents with novel mechanisms of action. The three new agents likely to have the greatest impact in the near future are the thymidylate synthase inhibitor ZD1694 (Tomudex), the topoisomerase I inhibitor irinotecan (Campto) and the new platinum compound, oxaliplatin (L-OHP). Promising response rates of 26 and 20% have been reported with ZD1694 in patients with advanced colorectal cancer in phase II and III studies, respectively. In a European phase II study, irinotecan has achieved response rates of 19% in chemotherapy-naive patients and 18% in pretreated patients with advanced disease. Oxaliplatin has mainly been investigated in combination with continuous infusion 5-FU, with response rates of 29-58%. Other agents currently in development include monoclonal antibodies (e.g. 17-1A and MN-14), protein synthesis inhibitors (e.g. RA 700) and angiogenesis inhibitors (e.g. PF 4).
Selective cytostatic and cytotoxic effects of glucosinolates hydrolysis products on human colon cancer cells in vitro.
Gamet-Payrastre L. Lumeau S. Gasc N. Cassar G. Rollin P. Tulliez J.
INRA, Laboratoire des Xenobiotiques, Toulouse, France.
Glucosinolates hydrolysis products are attracting increasing attention since many studies have suggested that they may be involved in the anticarcinogenic property of cruciferous vegetables. In this study, we show that diindolylmethane (DIM) and sulforaphane, produced during the hydrolysis of glucobrassicin and glucoraphanin, respectively, exert a dose-dependent cytotoxicity on human colon adenocarcinoma HT29 cells. Moreover, these products are able to inhibit quiescent cells to re-enter the cell cycle. Interestingly, our results clearly show that low doses of DIM and sulforaphane, although very effective on undifferentiated intestinal HT29 cells, do not affect the viability of the differentiated CaCo2 cells. The reversibility of their effects has also been tested and is discussed.
Antiproliferative activity of synthetic tetrapeptides, analogs of AS-I phytotoxin, towards cancer cell lines.
Liakopoulou-Kyriakides M. Stavropoulos G. Geromichalos G. Papazisis KT. Kortsaris AH. Kyriakidis DA.
Department of Chemical Engineering, Aristotle University, Thessaloniki, Greece.
The in vitro chemosensitivity of three cancer cell lines [HT29 (colon), HeLa (cervical) and T47D (breast)] to eight synthetic tetrapeptides, analogs of AS-I toxin, with phytotoxic effect on a series of plants was studied. Mouse fibroblast L929 cell line was also tested for chemosensitivity to these peptides. All cell lines were especially sensitive to Cys-Val-Gly-Glu tetrapeptide with IC50 values of 0.18, 0.3 and 0.63 mM for HT29, HeLa and T47D cells, respectively, whereas the IC50 value for the L929 cells was higher than 1 mM. Antiproliferative activity was also observed with peptides Tyr-Val-Gly-Glu and His-Val-Gly-Glu with IC50 values higher than those obtained for Cys-Val-Gly-Glu. For the rest of the peptides tested the IC50 values were found close to or higher than 3 mM.
Gemcitabine--a safety review.
Aapro MS. Martin C. Hatty S.
Oncology Service, Clinique de Genolier, Geneva, Switzerland.
Gemcitabine is a novel nucleoside analog with demonstrated efficacy across a range of solid tumors. This paper reviews the single-agent safety profiles of 979 patients in 22 completed clinical studies using a day 1, 8, 15 q 28 day, 800-1250 mg/m2 dose schedule. Hematological toxicity was mild with WHO grade 3 and 4 toxicities recorded for hemoglobin (6.8 and 1.3% of patients), leukocytes (8.6 and 0.7%), neutrophils (19.3 and 6.0%) and platelets (4.1 and 1.1%). Myelosuppression was short lived and rarely of clinical significance. Mucositis and alopecia were rare, and nausea and vomiting mild. Transient rises in transaminases, mild proteinuria and hematuria were common, but rarely clinically significant. Renal failure of uncertain etiology was reported in seven instances. Some patients (18.9%) experienced transient flu-like symptoms and mild fever was reported in 37.3% of flu patients. Peripheral edema was reported in 20.3% of patients in the absence of cardiac, hepatic or renal failure. Thus, gemcitabine is well tolerated and has a mild toxicity profile. Of nearly 11,000 protocol-defined injections, 94% were administered and only 14% were reduced. Grade 3 or 4 non-laboratory toxicities with a frequency of more than 1% were only seen for infection (1.2%), nausea and vomiting (18.4%), and pulmonary toxicity (1.4%).
The effect of combining antitubulin agents on differentiated and undifferentiated human colon cancer cells.
Carles G. Braguer D. Sabeur G. Briand C.
UPRES A-CNRS 6032, Faculty of Pharmacy, Marseille, France.
The cytotoxicity of sequential combinations of a taxoid [paclitaxel (TAX) or docetaxel (TXT)] with a vinca alkaloid [vinorelbine (NVB)] was compared in differentiated and undifferentiated HT29-D4 cells. Agents were titrated from low doses inducing no modification of microtubule network to high doses corresponding to the clinically relevant concentrations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtained synergism for low doses of both compounds [NVB (1-5 nM) and TAX (1-15 nM)], then additivity and finally antagonism when one of the compounds was at the concentration inducing mitotic block. The three patterns of results were also obtained with NVB/TXT combinations. For the synergistic combinations at the lowest concentrations, cytotoxicity occurred by apoptosis following mitosis. For differentiated cells, the most cytotoxic combinations were 1 microM TAX or TXT for 3 days followed by 1 microM NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 microM NVB for 3 days, the latter producing synergistic effects. Cytotoxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low sensitivity of differentiated cells to antitubulin agents and the difference in apoptotic pathways since mitosis is not involved in differentiated cells.
Determination of unbound platinum after oxaliplatin administration: comparison of currently available methods and influence of various parameters.
Gamelin E. Boisdron-Celle M. Lebouil A. Turcant A. Cailleux A. Krikorian A. Brienza S. Cvitkovic E. Larra F. Robert J. Allain P.
Department of Medical Oncology and Clinical Pharmacology, Centre Paul-Papin, Centre Regional de Lutte Contre le Cancer, Angers, France.
Variations in plasma protein binding may have profound effects on both disposition and activity of drugs, especially for those which are tightly bound to proteins, such as anticancer platinum derivatives. Methods of separation of the non-protein-bound fraction and some technical parameters may influence the results. We have compared ultrafiltration and ultracentrifugation, as well as the effect of potentially interfering factors, upon the determination of the plasma unbound platinum fraction after oxaliplatin administration to cancer patients. Ultrafiltration and ultracentrifugation provided very closely correlated results, so that either technique can be used. The ultrafiltration cut-off (3000-30,000 Da) devices, the type of tube for blood sampling and the type of anticoagulant (none, lithium heparinate or EDTA) did not influence the results markedly. In contrast, results were greatly influenced by freezing: erratic results were obtained on thawed plasmas when compared with those on fresh serum or plasma. Consequences may be important in usual practice, since many pharmacokinetic studies are carried out in multicentric trials with plasma processing centralized in one reference laboratory. The methods for the determination of protein-drug binding should be standardized and guidelines elaborated where optimal conditions for each type of binding assay are given.
The bisbenzylisoquinoline alkaloids, tetrandine and fangchinoline, enhance the cytotoxicity of multidrug resistance-related drugs via modulation of P-glycoprotein.
Choi SU. Park SH. Kim KH. Choi EJ. Kim S. Park WK. Zhang YH. Kim HS. Jung NP. Lee CO.
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Taejon.
The occurrence of resistance to chemotherapeutic drugs is a major problem for successful cancer treatment and reducing drug accumulation by P-glycoprotein (P-gp) is one of the major mechanisms of multidrug resistance (MDR). The present study was performed to evaluate the MDR-reversal abilities of two bisbenzylisoquinoline alkaloids, tetrandine (TET) and fangchinoline (FAN), compared with verapamil (VER), a well-known P-gp modulator. TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) reduced the paclitaxel (TAX) concentration required to achieve 50% inhibition of cell growth (EC50) to HCT15 (P-gp-positive) cells about 3100-, 1900- and 410-fold, and these compounds also reduced the EC50 value of actinomycin D (AMD) about 36.0-, 45.9- and 18.2-fold in the cells, respectively. Meanwhile, TET, FAN and VER had no effect on the cytotoxicity of the drugs to SK-OV-3 (P-gp-negative) cells. On the other hand, TET (3.0 microM), FAN (3.0 microM) and VER (10.0 microM) similarly enhanced the accumulation rates of rhodamine 123, a well known P-gp substrate, in HCT15 cells (200-250%). After efflux for 2 h with fresh medium, TET and FAN also enhanced the residual rate of rhodamine 123 about 5.0- and 2.6-fold in comparison with control, respectively. TET, FAN and VER could not affect the accumulation and residual rate of rhodamine 123 in SK-OV-3 cells. From the result, we conclude that TET and FAN enhanced the cytotoxicity of MDR-related drugs via modulation of P-gp.
Antitumor activity of KW-2170, a novel pyrazoloacridone derivative.
Ashizawa T. Shimizu M. Gomi K. Okabe M.
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co. Ltd, Shizuoka-Ken, Japan.
5-(3-Aminopropyl)amino-7,10-dihydroxy-2-(2-hydroxethyl)-aminoethyl -6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxy-chloride (KW-2170), a novel derivative of pyrazoloacridone, was selected and evaluated for its antitumor activity and toxicity in mice. KW-2170 exhibited antitumor activity superior to adriamycin (ADM) against Sarcoma 180, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in mice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed significant antitumor activity against 17 human tumor xenografts of a total of 24 tumors tested and the total tumor response rate by treatment with KW-2170 was significantly higher than that by ADM (70.8 versus 58.3%). In particular, human lung carcinoma was highly sensitive to KW-2170, and a marked tumor regression was observed on Lu-65 and Lu-99 human lung carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also high on these human carcinoma models in comparison with that of ADM. The best antitumor efficacy of KW-2170 was observed by a weekly treatment schedule followed by a single treatment schedule and a successive administration schedule also tended to be toxic to the hosts. KW-2170 exhibited very low cross-resistance against four lines of multidrug resistant tumors expressing high levels of P-glycoprotein, and the drug showed significant antitumor activity against ADM-resistant human ovary carcinoma A2780/ADM and against nasopharynx carcinoma KB-A1 xenografts which were not sensitive to ADM. These results indicate that KW-2170 has a very potent antitumor activity and is feasible as a new antitumor drug against ADM-refractory solid tumors in clinics.
Oxaliplatin combined to 5-fluorouracil and folinic acid: an effective therapy in patients with advanced colorectal cancer.
Gerard B. Bleiberg H. Van Daele D. Gil T. Hendlisz A. Di Leo A. Fernez B. Brienza S.
Department of Gastroenterology, ULB, Institut Jules Bordet, Brussels, Belgium.
Patients with colorectal carcinoma progressing after a 5-fluorouracil (5-FU)-containing regimen were eligible. One treatment cycle consisted of repeated administrations of 5-FU combined to folinic acid for six times and to oxaliplatin for three times over 50 days. 5-FU was given at the dose of 2.6 g/m2 as a continuous infusion over 24 h on days 1, 8, 22, 29 and 43 preceded by i.v. folinic acid (FA) at a dose of 500 mg/m2 over 1 h. Oxaliplatin was given 1 h after 5-FU at the dose of 130 mg/m2 over a 2 h infusion on days 1, 22 and 43. A total of 37 patients were treated according to this schedule. The rates of objective responses after the first and second treatment cycles were 28 and 17%, respectively, with rates of tumor growth control, i.e. including the stabilizations, of 55 and 28%. The median duration of response was 10 months and the median duration of stabilizations was 6 months. The median survival time from initiation of oxaliplatin-containing therapy is 10 months (2-28+). The median survival time from the diagnosis of metastatic disease is 24 months (2-40+). The main toxicities were leucopenia, diarrhea, fatigue and paresthesias. The combination of 5-FU/FA/oxaliplatin was well tolerated and appears as a meaningful therapy after failure of a previous 5-FU-containing treatment.
Phase II study of paclitaxel in pretreated advanced gastric cancer.
Cascinu S. Graziano F. Cardarelli N. Marcellini M. Giordani P. Menichetti ET. Catalano G.
Unita Operativa di Oncologia Medica, Azienda Ospedaliera S Salvatore, Pesaro, Italy.
Patients with advanced gastric cancer unresponsive or progressing after PELF chemotherapy (5-fluorouracil, leucovorin, cisplatin and epidoxorubicin) received paclitaxel at the dose of 225 mg/m2 every 3 weeks, over 3 h infusion. Thirty-six patients entered the study, and all of them were evaluable for response and toxicity. Toxicity was mild: apart from alopecia, grade 3 toxicities were leukopenia and thrombocytopenia in six patients, and grade 2 neurotoxicity in seven patients. Eight patients (22.2%, 95% CI: 9-35%) achieved an objective response, with a median duration of 5 months. Median survival time for all patients was 8 months. In 16 of 36 patients (44%), treatment determined a significant relief of symptoms. Out-patient paclitaxel given over 3 h may be effective as salvage treatment in patients with advanced gastric cancer refractory to first line chemotherapy.
Elevated expression of S100P, CAPL and MAGE 3 in doxorubicin-resistant cell lines: comparison of mRNA differential display reverse transcription-polymerase chain reaction and subtractive suppressive hybridization for the analysis of differential gene e
Bertram J. Palfner K. Hiddemann W. Kneba M.
Department of Hematology/Oncology, University of Gottingen, Germany.
Subtractive suppressive hybridization (SSH) and mRNA differential display reverse transcription-polymerase chain reaction (DDRT-PCR) were compared for their ability to detect the expression of drug-resistance associated genes in a doxorubicin-resistant and -sensitive colon carcinoma cell line (LoVo H67P). The expression pattern of more than 9000 bands obtained by DDRT-PCR were identical in both cell lines by more than 95%. Of the remaining differentially expressed DDRT-PCR products, 21 cDNA fragments were further analyzed after cloning. A total of 210 clones were sequenced resulting in 40 different sequences of which only five were differentially expressed as revealed by Northern blot analysis. SSH, on the other hand, resulted in 30 different sequences of 37 clones analyzed. Thirteen of 30 sequences (43%) could be identified by databank analysis (excluding expressed sequence tags) in contrast to nine of 40 clones (23%) obtained by DDRT-PCR. Of the clones identified by SSH, 60% exhibited a differential expression comparing the doxorubicin-resistant and -sensitive cell line, respectively, as compared to only 13% of the DDRT-PCR derived clones. The application of SSH resulted in the identification of differentially expressed genes in three doxorubin-resistant cell lines (LoVo DxR, ARH D60 and KB-V1) as compared to the sensitive parental cell lines. A significant higher expression of S100P, a protein involved in calcium metabolism, as well as MAGE 3 (melanoma antigen gene) was found in the resistant cell lines using this methodology. The expression of CAPL, a second protein involved in calcium metabolism, was only moderately elevated in the doxorubicin-resistant cells. We found that subtractive suppressive hybridization proved to be a more rapid and reliable method for the detection of differentially expressed mRNAs in our system.
A pilot study of fiberscopy-guided local injection of anti-cancer drugs bound to carbon particles for control of rectal cancer.
Hagiwara A. Hirata Y. Takahashi T.
First Department of Surgery, Kyoto Prefectural University of Medicine, Japan.
Rectal cancer patients with contra-indicatory risks may not be able to undergo surgery. In these cases the preferred treatment is chemotherapy. The present dosage formulation, consisting of an anti-cancer drug bound to activated carbon particles, was designed to deliver the anti-cancer drug at high concentration selectively to the injection site as well as to the regional lymph nodes and to improve survival of mice bearing cancer with nodal metastases, as compared to the same dose of aqueous anti-cancer drug in animal experiments. The present clinical trial includes two patients with histologically confirmed adenocarcinoma of the rectum and who had risks contra-indicating surgery. Carbon particles adsorbing anti-cancer drugs totaling 400 mg of methotrexate and 32 mg of mitomycin C in one patient and 100 mg of methotrexate and 8 mg of mitomycin C in another patient were injected into the cancer tissue under guidance of a colono-fiberscope. The rectal cancers were successfully reduced in size and controlled over 2 years or 6 months until the patients died from other causes. Side effect was mild. Local injection of this dosage formulation will be useful for the control of rectal cancer in patients who cannot undergo surgery.