Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna.

This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin's disease and diffuse large B cell lymphoma.In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent.

Uracil mustard and 5-fluorouracil combination chemotherapy: a historic record.

BACKGROUND: Uracil mustard and 5-fluorouracil (UM-FU) combination chemotherapy was used as one of the earliest combination chemotherapies in ovarian carcinoma from 1964 to 1971 at Yale New Haven Medical Center. METHODS: UM-FU was offered to patients with stage III and IV, histologically verified, ovarian carcinoma. Uracyl mustard was administered orally--1 mg/ kg, daily. 5-Fluorouracyl was administered every four weeks at 5 mg/kg for five days by intravenous infusion. RESULTS: Of a total 185 patients with ovarian cancer, 76 received UM-FU. Thirty-five patients had measurable disease. Fifteen (42%) showed objective response lasting three to 95 months, with decrease in size of masses and disappearance of ascites or hydrothorax. Their survival from diagnosis to death was 41 months. Twenty patients showed no response; their mean survival was 18 months. Three of the 76 patients who received UM-FU developed acute nonlymphocytic leukemia. CONCLUSION: UM-FU was effective in controlling ascites and hydrothorax and diminished intraabdominal masses. The discovery of adriamycin and then platinum led to more effective therapy and the use of uracil mustard was superseded. It is no longer available. The experience reported is of historic interest.

Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas.

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999-2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. 'S-1 and low-dose cisplatin therapy' without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, 'alternate-day S-1 regimen' may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. < or =Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.

The history, mechanism and clinical use of oral 5-fluorouracil derivative chemotherapeutic agents.

The role of oral chemotherapy has been getting expanded because of the potential advantage in patients' convenience and better quality of life as well as in cost-effectiveness as compared with intravenous chemotherapy. In this article, the history, mechanism of anti-tumor activity, and clinical use of oral chemotherapy using 5-fluorouracil (5-FU) derivative chemotherapeutic agents are reviewed. Pharmacological analysis has revealed that 5-FU, a basic chemotherapeutic agent widely used against a variety of malignant tumors, shows a time dependent anti-tumor activity, and that continuous maintenance of 5-FU concentration in blood is the optimal method in 5-FU administration. UFT, a combination drug of ftorafur (tetrahydrofuranyl-5-fluorouracil, tegafur, FT) and uracil, has been developed to have potent anti-tumor activity by maintaining higher 5-FU concentration in blood and tumor tissues for a long time. FT is a pro-drug that releases 5-FU continuously, and uracil is added to inhibit degradation of the released 5-FU. Clinically, oral administration of UFT has proved to be effective as an adjuvant therapy after surgery for some malignant tumors such as non-small cell lung cancer. Moreover, UFT has proved to be effective for inoperable advanced malignancies such as colorectal cancer, especially in combination with leucovorin or cisplatin. Recently, S-1, a more active oral 5-FU derivative chemotherapeutic agent has been developed in Japan. Several factors to affect anti-tumor effects and/or toxicities of 5-FU and the derivatives, such as thymidylate synthase activity, dehydropyrimidine dehydrogenase activity and p53 status, are also discussed in the article. In conclusion, oral administration of 5-FU derivatives such as UFT may have several clinical advantages over intravenous 5-FU administration.

Infusional 5-FU: historical evolution, rationale, and clinical experience.

The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment of a large spectrum of tumors, including all gastrointestinal cancers, breast cancer, head and neck cancer, and bladder cancer. Over these 4 decades, there has been an increased understanding of the optimal method and schedule of administration of 5-FU. Furthermore, the concept of pharmacomodulation and biochemical modulation of 5-FU to increase therapeutic efficacy has emerged as a new strategy in cancer chemotherapy. The specific mechanism by which 5-FU induces lethal injury may vary depending on the administration schedule or the type of biochemical modulation applied. The optimal infusion duration and dose intensity of 5-FU continues to be debated as does the question of the need for biochemical modulation when using infusional schedules. Infusional administration of 5-FU has become the gold standard in the treatment of head and neck cancer, esophageal cancer, gastric cancer (in Great Britain), and rectal and anal cancer. The recent availability of oral formulations for 5-FU in conjunction with the capability of manipulating the metabolism of 5-FU, particularly with dihydropyrimidine dehydrogenase (DPD) inhibitors, may provide a substantial incremental improvement in these therapies by eliminating the need for parenteral administration and the use of ambulatory infusion pumps.

Chemotherapy of colorectal cancer: history and new themes.

Since the clinical introduction of 5-fluorouracil (5-FU) in 1958, improvements in the treatment of advanced colorectal cancer have been modest. However, improvements in response rates have been demonstrated when 5-FU is administered in conjunction with leucovorin, and when methotrexate or trimetrexate is administered preceding 5-FU, indicating that higher response rates could be achieved by biomodulating the activity of 5-FU. Thus, significant emphasis has been placed on designing more effective 5-FU-based combination regimens. Novel agents, including the thymidylate synthase inhibitor raltritrexed and the topoisomerase I inhibitor irinotecan, also have demonstrated activity in colorectal cancer. Other new approaches include the administration of oral 5-FU prodrugs. The development of novel agents, new therapeutic approaches, and the refinement of existing agents and regimens in the clinic will likely improve response rates and, ultimately, patient survival. The history, current treatment options, and future opportunities for advances in chemotherapy for the treatment of colorectal cancer are discussed.

Systemic therapy in metastatic colorectal cancer.

Fluorouracil-based chemotherapy regimens have been utilized in metastatic colorectal cancer for more than 30 years. Early attempts at defining an optimal treatment schedule and use in combination with other drugs failed to significantly improve results. In contrast, the clinical effectiveness of fluorouracil has been improved by continuous infusion administration and modulation with folinic acid. Both approaches have increased the response rate compared with results achieved with traditional bolus schedules; the effect on survival has been less significant. Unfortunately, expense and, in some instances, toxicity have also been increased, which detracts from their overall usefulness. Clinical studies that evaluate fluorouracil chemotherapy in combination with biological-response modifiers are ongoing and will be areas of intense research during the next few years.