YOU ARE NOW CONNECTED TO THE TOXLINE (1981 FORWARD, NON-ROYALTY) FILE. ==COLON CANCER AND OXALIPLATIN== 1 AUTHOR de Gramont A AUTHOR Louvet C AUTHOR Andre T AUTHOR Tournigand C AUTHOR Raymond E AUTHOR Krulik M TITLE [Chemotherapy of colorectal cancers with metastases] SOURCE Presse Med; VOL 25, ISS 35, 1996, P1678-82 (REF: 33) ABSTRACT The chemotherapy of metastatic colorectal cancer has demonstrated a symptomatic benefit and a prolongation in survival. The modulation of 5-fluorouracil (5-FU) by leucovorin is the current standard treatment. The best protocols include 5-FU 24 or 48 hour continuous infusion on a weekly or bimonthly schedule. The response rate is about 30%, the median progression-free survival is 6 to 8 months and the median survival 10 to 15 months. The toxicity is moderate. New drugs are available or under evaluation: 5-FU prodrugs, raltitrexed, CPT11, oxaliplatin, trimetrexate. Synergisms with 5-FU allow to consider more effective polychemotherapies. 2 AUTHOR Labianca R AUTHOR Pessi A AUTHOR Facendola G AUTHOR Pirovano M AUTHOR Luporini G TITLE Modulated 5-fluorouracil (5-FU) regimens in advanced colorectal cancer: a critical review of comparative studies. SOURCE Eur J Cancer; VOL 32A Suppl 5, 1996, PS7-12 (REF: 55) ABSTRACT Several modifications to the administration schedule of 5-fluorouracil (5-FU) alone or in combination with other agents have been investigated in advanced colorectal cancer. Biochemical modulation of 5-FU with leucovorin (LV) increases response rate compared with 5-FU alone, but without improvement of overall survival. The best treatment schedule and optimal dose of LV remain unclear, although low doses seem equally as effective as high doses, with the advantage of reduced cost. Methotrexate can increase the activity of 5-FU to a similar degree as LV and a recent meta-analysis showed a slight improvement in survival. The combination of 5-FU + interferon has been disappointing, with phase III trials showing similar activity to 5-FU + LV, but with high toxicity. Other modulators (e.g. hydroxyurea, N-phosphonacetyl-L-aspartate, dipyridamole) show promising but sometimes conflicting results. Standardisation of assessment criteria should be considered when comparing these data to the activity of new drugs such as 'Tomudex' (raltitrexed, previously known as ZD1694), CPT-11 and oxaliplatin. 3 AUTHOR Van Cutsem E TITLE A glimpse of the future. new directions in the treatment of colorectal cancer. SOURCE Eur J Cancer; VOL 32A Suppl 5, 1996, PS23-7 (REF: 55) ABSTRACT This paper overviews new directions in colorectal cancer therapy, focusing on adjuvant therapy, new cytotoxic agents and novel approaches. Reduced mortality with adjuvant therapy is mainly achieved in resectable colorectal cancer, using regimens of 5-fluorouracil (5-FU) plus leucovorin, 5-FU plus levamisole and 5-FU plus radiation. Not all patients are suitable for adjuvant therapy, and a better definition of prognostic factors will improve selection of patients for therapy. Several thymidylate synthase inhibitors are in development, including 'Tomudex' (raltitrexed, previously known as ZD1694), which has reached phase III studies, LY 231514, AG 331, AG 337, BW 1843 U89 and ZD 9331. Topoisomerase I inhibitors (e.g. CPT II, topotecan), ethynyluracil, oxaliplatin and 5-FU prodrugs are also promising therapeutic agents. Novel approaches include angiogenesis inhibitors, drugs which can stimulate apoptosis, generation of cytotoxic drugs from non-toxic prodrugs at tumour sites and conjugation of anti-tumour agents to polymeric carriers. Various modalities of specific and non-specific immunotherapy are also under research. These advancements promise improvements in the prognosis of colorectal cancer patients. 4 AUTHOR Schmoll HJ TITLE Development of treatment for advanced colorectal cancer: infusional 5-FU and the role of new agents. SOURCE Eur J Cancer; VOL 32A Suppl 5, 1996, PS18-22 (REF: 30) ABSTRACT Despite the fact that it was first introduced as a cancer treatment over 30 years ago, the mainstay cytotoxic agent for the treatment of metastatic colonic cancer is still 5-fluorouracil (5-FU). However, even after all this time, there is still no standard schedule for 5-FU administration which is recognised by the oncology profession. Bolus infusion remains the most popular choice, but recent investigations into short- and long-term continuous infusion schedules of 5-FU have offered advantages in terms of objective response rates and toxicity. In addition, combination infusion regimens (whereby the effectiveness of 5-FU is modulated through its co-administration with other agents or chronomodulation) are becoming accepted, although, once again, there is no recognised standard treatment regimen. This paper reviews the data from those non-comparative studies in which 5-FU has been administered as monotherapy, and relates this to data from studies of 5-FU co-administration with folinic acid and interferon. Data from other treatment regimens, which include topoisomerase I inhibitor schedules and chronomodulation of 5-FU with oxaliplatin, are presented. The advantages and disadvantages of these different regimens based upon these non-comparative data, and their position relative to standard therapies, are discussed. The likely developments with regard to the clinical and health-economic requirements for newer treatment are outlined. 6 AUTHOR Weiss RB AUTHOR Christian MC TITLE New cisplatin analogues in development. A review. SOURCE Drugs; VOL 46, ISS 3, 1993, P360-77 (REF: 109) ABSTRACT Cisplatin was discovered to have cytotoxic properties in the 1960s, and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. Since the early seminal work in the preclinical and clinical development of this drug, several thousand analogues have been synthesised and tested for properties that would enhance the therapeutic index of cisplatin. About 13 of these analogues have been evaluated in clinical trials, but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. However, carboplatin has afforded benefit only in reducing some cisplatin toxicities; it has not enlarged the spectrum of platinum-sensitive cancers, nor has it proved active in cisplatin-resistant cancers. The major obstacle to the efficacy of cisplatin or carboplatin is platinum resistance, either innate or acquired. The mechanisms of this resistance have been under intense study, and many of the cisplatin analogues synthesised in the past decade have been designed specifically with the hope of overcoming platinum resistance. The mechanism of the cytotoxic activity of platinum complexes has also been studied intensely. Recently synthesised analogues have been designed to interact with DNA in a manner different from cisplatin and carboplatin, with the desire of finding new structures with a superior or wider spectrum of antitumor efficacy. Most recently, water soluble platinum complexes that retain antitumour activity, but that can be effectively absorbed after oral administration, have been synthesised with the goal of improving patient quality of life. Nine platinum analogues are currently in clinical trials around the world (ormaplatin [tetraplatin], oxaliplatin, DWA2114R, enloplatin, lobaplatin, CI-973 [NK-121], 254-S, JM-216 and liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyc- lohexane platinum (II) [LNDDP]). Some of these analogues only represent attempts to reduce cisplatin toxicity and/or allow administration without forced hydration and diuresis, which carboplatin already does. Others are 'third generation' complexes shown to have limited or no cross-resistance with cisplatin in preclinical studies. They are being tested clinically with particular attention to this highly desirable property.(ABSTRACT TRUNCATED AT 400 WORDS) 3 AUTHOR Tashiro T AUTHOR Kawada Y AUTHOR Sakurai Y AUTHOR Kidani Y TITLE Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane)platinum (II): new experimental data. SOURCE Biomed Pharmacother; VOL 43, ISS 4, 1989, P251-60 ABSTRACT Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II) (l-OHP), was studied. This water-soluble platinum complex showed a more prominent life-prolonging effect on a mouse leukemia L1210 than cisplatin (DDP). By an intermittent treatment schedule cured mice were observed at the optimal dose. In addition, a subline of L1210 having a 40-fold resistance to DDP (L1210/DDP) showed lack of cross-resistance to l-OHP both in vivo and in vitro. Especially in vivo l-OHP was more active against L1210/DDP than against the original L1210, and all mice were cured at doses of 6.25 and 3.12 mg/kg. l-OHP was also effective against several mouse tumors such as P388 leukemia, B16 melanoma, Lewis lung carcinoma, colon 26 and colon 38 adenocarcinomas, and M5076 fibrosarcoma, though its antitumor spectrum was somewhat different from that of DDP. The synthesis of both DNA and RNA in L1210 cells was inhibited by about 50% with exposure to 10 microM of l-OHP for 1 h, followed by postincubation in drug-free medium for 6-24 h, while only the inhibition of DNA synthesis was observed by DDP in the same experiment. If severe toxicity is not observed in preclinical study, l-OHP expected to be a new clinically active Pt complex. 2 AUTHOR Christian MC TITLE The current status of new platinum analogs. SOURCE Semin Oncol; VOL 19, ISS 6, 1992, P720-33 (REF: 91) ABSTRACT Nine platinum analogs are currently in clinical development, including three that contain the diaminocyclohexane substituent and five that contain the cyclobutanedicarboxylato leaving group. Many of them have shown activity in at least one cisplatin (CDDP)-resistant cell line, most commonly L1210 murine leukemia. In addition, most were less nephrotoxic than CDDP in preclinical evaluations. While these agents share certain key structural similarities, there are important differences in their toxicity profiles that may be exploitable in future combination therapies. Though neuropathy has been a troubling toxicity with two of the three diaminocyclohexane (DACH) compounds, it differs in that it appears to be less chronic and cumulative with oxaliplatin (I-OHP), which is also associated with much less myelosuppression. Of the cyclobutanedicarboxylato compounds that are structurally related to carboplatin (CBDCA), there are several notable differences. For several compounds, isolated neutropenia has been dose-limiting and thrombocytopenia, which is common with CBDCA, has been uncommon. Like CBDCA, neurotoxicity has not been an issue with this group. Therefore, the potential for dose escalation with a colony stimulating factor (CSF) appears enhanced. Furthermore, promising early clinical leads, such as the substantial response rates in cervix and head and neck cancers with 254-S and in patients with colon cancer using circadian modulation of I-OHP, require careful evaluation. Preclinical synergy data are also cited that suggest other potential clinical leads. The development of a number of these agents has been complicated by unanticipated issues, including unexpected chronic dose-limiting neurotoxicity with ormaplatin (OP), formulation and stability problems with liposomal-neodecanoato-diaminocyclohexane platinum (II) (L-NDDP), and problematic nephrotoxicity with zeniplatin (ZP). However, several of these new compounds are likely to enter broader phase II and III development and should provide important information not only about the utility of the agents themselves but also about the predictive value of some of these preclinical models of CDDP resistance. 2 AUTHOR Slevin ML TITLE Adjuvant therapy for colorectal cancer SOURCE Br. Med. J.; VOL 312 ISS Feb 17 1996, P392-393, (REF 15) ABSTRACT IPA COPYRIGHT: ASHP A summary of clinical studies evaluating fluorouracil alone or with leucovorin (folinic acid) and/or levamisole in the therapy of colorectal neoplasms is presented, the availability of 2 new agents, irinotecan (CPT11) and oxaliplatin, for these types of neoplasms is reported, and future developments in this area of research are briefly discussed; trials of the use of fluorouracil alone by portal vein infusion are included in the discussion of clinical studies.