Interactive effects among antifungal and antineoplastic drugs contributed to toxicities when combinations of these drugs were used to inhibit the growth of five Candida spp. Drug interactions were measured by growth inhibition in both liquid and solid media, by viable cell counts and by examination using scanning electron microscopy. Large cooperative effects on toxicity were demonstrated between some antineoplastic and antifungal drugs. For example, positive cooperativity was seen between the antineoplastic drug 5-fluorouracil and combinations of the antifungal agents amphotericin B and miconazole nitrate. Smaller, and often negative, interactions occurred between the antineoplastic drug cyclophosphamide and antifungal drugs. The levels of drugs required for inhibition in combination drug treatments were critically dependent upon the ratios as well as the absolute concentrations of the drugs tested. Drug combinations were selected which inhibit yeast growth at concentrations far below the individual MIC of the drugs. These combinations may prove of value in clinical treatments of cancer patients infected by Candida.

Cancer therapy often entails the use of combinations of antineoplastic agents and/or radiotherapy with the aim of reducing tumor cell populations with minimal side effects (1). These treatments render patients deficient in all known parameters of immune defenses and, as such, predispose them to infection (9). Thus, combinations of one or more antimicrobial agents together with one or more antineoplastic drugs are frequently used in treatment. Taking into consideration the high incidence of yeast infections, particularly those due to Candida spp., among cancer patients (8,11,12,16), it is important to investigate the magnitude of interactions among the drugs used in combined antifungal and anticancer treatments.Both antineoplastic and antifungal agents cause undesirable side effects as a result of their high toxicities. Accordingly, a major goal in drug therapy has been to select drug combinations with synergistic action. Although interactions among drugs when used against microorganisms are well documented (2,7,10,14,15,17,19,20,22, 25), studies of interactive effects among antineoplastic and antifungal agents have not yet been reported.Studies investigating the effects of combinations of drugs on microorganisms have generally been limited to tests of only two drugs. Frequently, analyses are made in a onefactor-at-a-time fashion in which the concentration of a single drug is varied in the presence of a constant level(s) of the second. Such experiments have provided valuable information about interactive properties of the drugs, but cannot be used to quantitatively define interactions or to provide information about interactive effects at concentration levels other than those tested. The common approach to solving this dilemma has been to run tests at more concentrations, but the possible number of trials becomes prohibitive (4). A better approach to tests for two-factor interactions has been to use the so-called checkerboard titration, in which concentrations of both drugs are varied simultaneously. Mathematical treatment of this type of data can yield a quantitative * Corresponding author. description of all main and interactive effects of drug action. However, because of the number of tests involved, checkerboard titration becomes impractical for combinations of three or more drugs.There is, however, an important need for testing combinations of more than two drugs. Berenbaum (4) has devised a method for determination of the level of synergy or antagonism for combinations of several drugs with much less effort than would be required in a checkerboard titration. Odds (22) has used the Berenbaum method to study interactions among four antifungal drugs in inhibiting 11 fungal strains. The results clearly show drug interactions and also show the importance of using different assay procedures and conditions which may affect interpretations of the magnitudes of the interactions. Odds (22) draws attention to the power of the Berenbaum method in defining multiple drug responses and, simultaneously, points out some of ...

The effects of combinations of antifungal and antineoplastic drugs on inhibition of the growth of yeasts which commonly infect cancer patients have been analyzed. It was shown that (i) inhibitory drug combinations could be selected in which all drugs were at levels far below their individual MICs; (ii) interactive effects among antineoplastic and antifungal drugs may be very large; (iii) optimum combinations of drugs for inhibition of yeast growth depended upon both the relative and absolute concentrations of the drugs in the mixture; (iv) drug combinations which were effective at low levels in inhibiting one test yeast were also generally effective against other species, but the levels of susceptibilities and, to a lesser extent, the best ratios of drugs in the test combinations varied with species; and (v) to quantitatively evaluate drug interactions, it is necessary to carefully define and control all experimental conditions, absolute and relative concentrations of drugs used, and the organisms tested.

Between 1968 and 1981, 78 children younger than age 15 years were diagnosed, staged, treated, and followed up for a minimum period of 2 years. Most cases (64%) were in their first decade and the male-to-female ratio was 1.9:1. Mixed cellularity type occurred in 49% and nodular sclerosis in 32%. Lymphocytic depletion type was rare and occurred in only 4% of the cases. More than one half (53%) had Stages III and IV at presentation. The mediastinum was involved in 38%. The treatment of Stages I and II was mainly by radiotherapy, and Stages III and IV by combination of radiotherapy and chemotherapy. The total survival was 75% and relapse-free survival was 53%. Since 1975, lymphography became a routine investigation and staging laparotomy was performed in selected case. The mantle field was extended to include the para-aortic bar and spleen in Stage II with enlarged mediastinum, Stage IIIs after laparotomy, and cases in which laparotomy was thought to be indicated but was not performed. The new policy resulted in marked improvement in survival (from 56% to 87%) and relapse-free survival (from 32% to 70%). The stage at presentation was the main prognostic factor, although in the second period of the study, the difference between Stage I and II disappeared.

Serum levels of AFP, hCG and CEA were initially and serially measured in 59 patients with testicular germ cell tumors, and serially in 37 with ovarian and 3 with extragonadal germ cell tumors. Patients with seminoma/dysgerminoma or mature teratoma had normal serum AFP and sporadically slightly elevated hCG. Some patients with embryonal carcinoma, pure or with admixture of seminoma, had serum AFP elevated to maximum 100 U/ml, yet its use for monitoring therapy was limited. Patients with yolk sac tumors had elevated AFP and sometimes CEA levels, those with choriocarcinoma had elevated hCG, and those with compound tumors had one or more of the markers highly elevated. High AFP and/or hCG levels indicated the presence of the relevant tumor cells both in the primary and in residual tumor and/or metastases, also those missed in histological material, and thus were useful in restaging. Unfortunately, their absence in serum did not exclude the presence of marker-negative subpopulations of tumor cells. Changes in marker values paralleled the effects of treatment: the level increasing from any nadir heralded recurrence in patients in remission; elevated or increasing levels during therapy implied resistance to the therapy; decreasing levels indicated regression even though a return to the normal range did not mean eradication of all tumor cells.