Several new anthracyclines have been recently made available for clinical use or for clinical trials. Each molecule is characterized by original metabolic and pharmacokinetic features, which can be compared to those of the reference anthracyclines, doxorubicin and daunorubicin. Idarubicin is transformed into idarubicinol to a high extent, similarly to the transformation of daunorubicin to daunorubicinol, whereas the 13-dihydroderivatives of esorubicin, epirubicin or pirarubicin are present in plasma at lower levels than the parent drugs. Epirubicin is the only anthracycline able to form glucuronides, and pirarubicin can be transformed into doxorubicin itself. The elimination half-life of epirubicin or esorubicin is similar to that of doxorubicin (30 h) and the elimination half-life of unchanged idarubicin or pirarubicin is shorter (15-20 h). The novel anthracyclines have generally a higher plasma clearance than doxorubicin or daunorubicin, and a higher volume of distribution. Less than 10% of the injected dose of any anthracycline is found in urines, the major elimination pathway being the bile. The knowledge of anthracycline pharmacokinetics may allow the prediction of their behavior when special administrations are used (continuous infusion, locoregional therapy...).

The authors report a case of successful pregnancy 8 years after surgery and chemotherapy for biliary cancer with secondaries in the liver. The authors, in considering this case, have analysed the sequelae of chemotherapy for cancer on fertility. They discuss the need to preserve the ability to produce oocytes in young women who need treatment for cancer.

A paradoxical effect of radiotherapy and chemotherapy for cancer is that some of these treatments can themselves cause new cancers. Most epidemiologic methods can be applied successfully to the investigation of this problem and this paper reviews various approaches that have already been used by various researchers. The authors first review the more traditional methods, i.e., cohort and case-control studies and they then describe designs that have been proposed more recently, such as case-cohort studies. A distinction is established between internal comparisons, carried out within the study population, and external comparisons, in which a general population external to the population under study is used as the reference category. This presentation is mainly aimed at investigators using tumor registry data. However, the general principles formulated here are easily generalized to contexts other than that of registries.

The authors studied distraction osteogenesis in an animal subjected to prolonged anti-mitotic chemotherapy (Methotrexate and Doxorubicin). This chemotherapy decreased osteogenesis (essentially at the expense of external regeneration) though without inhibiting it totally. Distraction bone consolidation is thus possible in the animal, permitting reconstruction of limb segments by mobilization of an axial fragment in accordance with the Ilizarov technique.

Fifteen patients with hepatocellular carcinoma were administered elliptinium acetate in a phase II trial. A dose of 80 mg/m2/day was administered during 3 consecutive days, every 3 weeks. According to WHO criteria regarding response, no objective responses were observed. The major toxicity was dryness of the mouth which occurred in 73% of patients, on addition, one case of hemolysis was documented in spite of a systematic search for anti-elliptinium antibodies prior to each injection. In conclusion, elliptinium acetate has no valuable therapeutic impact on the treatment of hepatocellular carcinoma.

Most experimental data clearly suggest that antitumor agents including DNA intercalative molecules (acridine derivatives, ellipticine and derivatives), or non intercalative ones (epipodophyllotoxines), exert their cytotoxic activity by stabilizing DNA-Topoisomerase II complexes. This phenomenon can be revealed by the presence of DNA breaks upon protein denaturing treatment. In this work, BD-40, an ellipticine analog has been shown to interact in vivo with Topoisomerase II. Moreover, cleavage sites generated by the drug treatment in human proto-oncogene c-myc appear to be mostly localized in the 5' end of the gene locus, which contains regulatory elements. Some of these sites are in a striking correspondence with DNAse I hypersensitive sites, which reportedly reflect the state of activity of genes.

Circadian rhythms characterize murine tolerance for 18 anticancer agents, including radiations and chemotherapeutic drugs. Such rhythms usually exhibit a large amplitude. Moreover, the circadian time of highest host tolerance for several cytostatics was similar to that of their optimal antitumor effectiveness in four different experimental models. Mechanisms of such rhythms involve predictable temporal changes in drug pharmacokinetics as well as rhythms in the susceptibility of both tumor and host tissues. Studies performed in mice or rats led to an adequate prediction of the optimal time to administer adriamycin, 4'tetrahydropyranyl-adriamycin and cis-dichlorodiammine platinum, provided that the rest-activity cycle of either species be considered. Since the dosing time of these agents also influenced largely the extent of human tolerance for these drugs, the extension of circadian timed therapy appears as inescapable. Programmable delivery systems have been developed to render such goal feasible, and their need has been emphasized in preliminary studies. Since interindividual differences may characterize, to some extent, host chronotolerance, and to a larger extent, tumor chronosusceptibility, a circadian monitoring of marker variables ("marker rhythms") constitutes a further challenge for individualizing cancer chronotherapy.

In a phase I-II trial, 38 patients with acute myeloid leukemia (AML) were given single drug induction therapy with aclarubicin (ACM) according to two dosing schedules: treatment 1: 10 to 30 mg/m2/d to a maximum total dose of 300 mg/m2 or until development of unacceptable toxicity: treatment 2: 15 mg/m2/d in ten-day courses separated by ten-day intervals. Response rates were 15% with treatment 1 and 44% with treatment 2 (overall response rate 34%). Complete remission (CR) was achieved in 6 patients who had previously failed to respond to adriamycin (ADM). Toxicity was more frequent and more severe in those patients given more than 150 mg/m2 ACM per course. The main side effects were oropharyngeal mucositis and diarrhea. Three patients exhibited T wave inversion and one had an episode of auricular flutter. In a separate trial in 16 patients with AML we used cyclic chemotherapy combining ACM (20 mg/m2/d) and ARA-C (200 mg/m2/d) for seven consecutive days. Complete remission rate was 50%. Severe ventricular rhythm disorders were seen in two patients. In a phase I-II study, 19 patients with acute lymphoid leukemia (ALL) and 8 patients with non-Hodgkin lymphoma (NHL) were given ACM alone according to the regimen designated treatment 1 described above. Response rates were 11% (2/19) in ALL and 25% (2/8) in NHL. A review of the literature is presented in the discussion of the original trials reported herein.

Association between radiotherapy and anthracyclines (especially adriamycin) early showed major toxicity on critical normal tissues so that its antitumor activity was concealed. This toxicity proved to be acute toxicity, recall phenomenon and cardiac toxicity. Clinical and experimental studies showed synergistic effect when drug and radiation are administered concomitantly and additive effect in sequential administration. So concomitant association must be rejected. The main point is the time interval between adriamycin injection and radiotherapy (at least seven days). These conditions are respected when alternating treatment schedule is applied: radiation split courses are integrated between two chemotherapy cycles including adriamycin. At this time new anthracycline analogs were not associated to radiotherapy.

Since the first discovery of antitumor properties of daunorubicin in 1962, several hundreds of anthracyclines have been evaluated. In 1969, the primary screening on L1210 leukemia allowed to detect doxorubicin which is more active than daunorubicin and has been found clinically active on several human solid tumors. Therefore, L1210 leukemia appeared to be a useful model for evaluating experimental antitumor activity of anthracyclines, indicating a possible correlation between this model and the clinic. Analogs which are equally or more active than doxorubicin in the primary screening are tested in the secondary screening, then eventually in models of cardiotoxicity in order to evaluate their therapeutic index. The secondary screening includes murine solid tumors (B16 melanoma, Lewis lung carcinoma, mammary adenocarcinomas, colon adenocarcinomas 26 and 38) and human tumor xenografts into nude mice or under the renal capsule of normal mice (LX1, lung - CX1, colon - MX1, breast). Various tumor localizations (i.p., i.v., s.c., i.m., i.c.), various routes of administration (mainly i.v. and p.o.), various schedules of treatment (early or delayed, repeated or intermittent) and models of polychemotherapy are used to obtain a better evaluation of the compound. P388 leukemia resistant to doxorubicin is useful to test cross resistance in vivo and also to screen compounds able to reverse this phenomenon. Until now, 17 new anthracyclines have been introduced into clinical trials. Aclacinomycin has a different mechanism of action from that of doxorubicin (induction of tumor cell differentiation, inhibition of B and T suppressor lymphocytes); it is less myelotoxic and it is not mutagenic in vitro. THP-doxorubicin is more active than doxorubicin against L1210 leukemia and some solid tumors; it seems less cardiotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical treatment of skin ulcers from extravasation of chemotherapeutic agents produces a chronic ulcer. The origin of the disease and the techniques of wide local excision and of skin cover are discussed.

This review is not intended as a complete study of the nephrotoxicity of chemotherapy agents used in the treatment of cancer. The number of these drugs that are cytotoxic has considerably increased in the last few years and our information is incomplete for many of them. We therefore reviewed the observations reported in the literature. Cis-platinum, streptozotocin, methotrexate at high doses, mithramycin and mitomycin are highly nephrotoxic. Other drugs, such as nitrosoureas, celiptium are less nephrotoxic while some appear to rarely induce nephrotoxicity. Anticancer drug nephrotoxicity is characterized by its particular insidiousness, its time of occurrence and its evolution. Since no clinical manifestations accompany the lesions, nephrotoxicity must be sought routinely. It can occur early or late, may be constant as of the first course or appear only after a certain cumulative dose and even occasionally after such a long interval that its cause may appear to be in doubt. The severity of this nephrotoxicity ranges from the usual first minor urinary anomalies to terminal renal failure. The pathophysiogenic mechanisms of the nephrotoxicity remain in most cases obscure. The mode of penetration into the cells is not known. There are fewer data on the interaction between the toxic agent and the cellular metabolism. In most cases, the drug itself in unchanged form does not seem to be the causative agent, which appears rather to be its metabolite. These metabolites are not always identified. Thus nephrotoxicity of antitumoral agents has not been given sufficient attention. Only better knowledge of their action within the kidney will eventually lead to progress in preventing their harmful side effects.