Showing papers on "Doxorubicin published in 1983"

Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation.

Abstract: Antitumor drugs such as doxorubicin have been encapsulated into liposomes as a means of enhancing activity and reducing toxicity. The present study was initiated to determine whether chronically administered liposome-encapsulated doxorubicin would be less toxic than the free drug. Doxorubicin was prepared in positively charged cardiolipin liposomes, and 1.75 mg/kg was given i.v. to each of five beagles. A second group received the free drug at 1.75 mg/kg. Additional animals received i.v. injections of either doxorubicin-free liposomes or 0.9% NaCl solution. All substances were given at 3-week intervals, and the experiment ended 1 week after the seventh injection (total dose, 12.25 mg/kg). A temporary reduction in food consumption was noted during the first few days after the administration of either form of doxorubicin. The effect was more severe in the dogs given free doxorubicin, and body weight decreased significantly only in this group of animals. Three dogs given free doxorubicin died or were killed before the end of the study because they were in poor condition. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all five dogs given free doxorubicin. The severity of the lesions ranged from 2 to 4 (average, 3.4). In contrast, no abnormalities were found in any of the hearts from dogs given the liposomal doxorubicin. The most obvious general toxic effect caused by administration of free doxorubicin was alopecia, which was entirely prevented when doxorubicin was encapsulated into liposomes. At the dosage regimen utilized, liposomal doxorubicin and free doxorubicin exerted comparable degrees of bone marrow suppression. Thus, liposomal encapsulation of doxorubicin decreased cardiac and other toxic effects elicited by free doxorubicin. Whether this advantage can be translated into effective antineoplastic activity will need further evaluation.

Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities

Abstract: Sixty-five patients with high-grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high-dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow-up of 653 days revealed an advantage in continuous disease-free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one-sided Mantel-Haenszel test). The continuous disease-free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty-eight percent of patients had limb-sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease-free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four-year follow-up, reveals an improvement in disease-free and overall survival due to chemotherapy (P less than 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment adult patients with soft tissue sarcomas of the extremities.

Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study.

Abstract: Previously untreated patients with multiple myeloma were entered on a randomized clinical trial to determine whether the use of alternating combination chemotherapy, including vincristine, doxorubicin, alkylating agents, and prednisone (160 patients) was more effective than conventional chemotherapy with melphalan and prednisone (77 patients), and whether the addition of the immunomodulating agent levamisole to maintenance chemotherapy enhanced the survival of patients achieving remission. The treatment groups were well matched for all major factors. The more aggressive chemotherapy was more effective at inducing remission, with a significantly higher proportion of patients achieving at least 75% tumor mass regression (53% with alternating combinations versus 32% with melphalan-prednisone, p = 0.002). Furthermore, the median survival was increased to 43 months with alternating combination chemotherapy as compared to 23 months with melphalan-prednisone (p = 0.004). After six to 12 months of induction therapy, 84 patients achieving remission were rerandomized to receive maintenance chemotherapy alone or with the addition of levamisole. The survival from the start of maintenance therapy was longer in patients receiving the added levamisole than with chemotherapy alone (p = 0.01). These findings support the use of aggressive multiagent chemotherapy for remission induction in patients with advanced-stage multiple myeloma.

Improved therapeutic benefits of doxorubicin by entrapment in anionic liposomes.

Abstract: When used as drug carriers, anionic liposomes can reduce the chronic cardiac toxicity and increase the antileukemic activity of doxorubicin (DXN; Adriamycin). Continuing investigations, reported here, have now established the therapeutic benefits of this mode of drug delivery. Liposome encapsulation caused a prolonged elevation in DXN plasma levels and a 2-fold reduction in the exposure of cardiac tissue to the drug. This reduction, however, was not proportional to the substantial decrease in chronic heart toxicity observed in the earlier study. In vivo studies have demonstrated that the entrapped drug retains its full activity against Sarcoma 180 and significantly increases its action against Lewis lung carcinoma, as measured by reduced tumor volume. The increased antineoplastic activity was again not proportional to the increased association of drug with tumor tissue. The effect of liposome entrapment on the immune-suppressive activity of DXN was also examined to determine if factors other than the direct delivery of drug to tumor tissue might improve the therapeutic response. The suppression of the humoral immune response and peripheral leukocyte counts by free DXN was nearly abolished when the drug was administered in the liposome form. These experiments suggest that the improved therapeutic effect of encapsulation may be the outcome of three different mechanisms: (a) altered disposition into subcellular compartments, which reduces cardiotoxicity; (b) increased plasma drug exposure to tumor cells; and (c) significant reduction in the immune suppressive activity of DXN.

Plasmin-activated prodrugs for cancer chemotherapy. 2. Synthesis and biological activity of peptidyl derivatives of doxorubicin

Abstract: We have synthesized peptidyl prodrugs of doxorubicin (Dox) designed to be selective substrates of plasmin. Such prodrugs might be locally activated by the elevated levels of plasmin produced near many solid tumors under the action of tumor-associated plasminogen activators. One such prodrug, 3'-(D-Val-Leu-Lys)-Dox, was obtained via a mixed-anhydride coupling with isobutyl chloroformate between the protected peptide Fmoc-D-Val-Leu-N epsilon-Fmoc-Lys-OH and doxorubicin, followed by removal of the Fmoc groups with anhydrous ammonia. Compared to doxorubicin, the prodrug showed about a 7-fold improved selective cytotoxicity against chicken embryo fibroblasts transformed with the Rous sarcoma virus (which produce high levels of plasminogen activator) compared to normal cells (which produce low levels of plasminogen activator). However, the prodrug was a very poor plasmin substrate, and although in vivo tests against the murine B16 melanoma showed that the prodrug was active, the maximum T/C obtained was less than that achieved by doxorubicin even at 25 times the molar concentration of prodrug. Qualitatively similar results were obtained for a far more hydrophobic prodrug, 3'-(Boc-Val-Leu-Lys)-Dox. These results demonstrate that peptidyl prodrugs of doxorubicin designed as plasmin substrates are more selective anticancer agents in vitro than doxorubicin itself but that the bulky anthracycline moiety probably prevents efficient plasmin-catalyzed conversion to the active parent drug, so that, in their present form, these drugs are not potent enough to allow a determination as to whether or not they are more selective in vivo.

Improved Therapeutic Benefits of Doxorubicin by Entrapment in Anionic

Abstract: When used as drug carriers, anionic liposomes can reduce the chronic cardiac toxicity and increase the antileukemic activity of doxorubicin (DXN; Adriamycin). Continuing investigations, reported here, have now established the therapeutic benefits of this mode of drug delivery. Liposome encapsulation caused a prolonged elevation in DXN plasma levels and a 2fold reduction in the exposure of cardiac tissue to the drug. This reduction, however, was not proportional to the substantial decrease in chronic heart toxicity observed in the earlier study. In vivo studies have demonstrated that the entrapped drug retains its full activity against Sarcoma 180 and significantly increases its action against Lewis lung carcinoma, as measured by reduced tumor volume. The increased antineoplastic activity was again not proportional to the increased association of drug with tumor tissue. The effect of liposome entrapment on the immune-suppressive activity of DXN was also examined to determine if factors other than the direct delivery of drug to tumor tissue might improve the therapeutic response. The suppression of the humoral immune response and peripheral leukocyte counts by free DXN was nearly abolished when the drug was administered in the liposome form. These experiments suggest that the improved therapeutic effect of encapsulation may be the outcome of three different mechanisms: (a) altered disposition into subcellular compartments, which reduces cardiotoxicity; (b) increased plasma drug exposure to tumor cells; and (c) significant reduction in the immune suppressive activity of DXN.

Doxorubicin (adriamycin) cardiomyopathy.

Abstract: Despite its vast utility in clinical oncology, the use of doxorubicin hydrochloride (Adriamycin) is limited by a potentially fatal cardiomyopathy. The following critical review, which examines the natural course, histopathologic effects, risk factors and monitoring indicators of this toxicity, also analyzes recent research of proposed mechanisms, including free radical formation with depletion of detoxifying enzymes, inhibition of vital enzyme systems and alterations in relative calcium concentrations. Prevention of the adverse reaction has been attempted by using such agents as alpha-tocopherol, selenium sulfide, coenzyme Q(10), sulfhydryl donors, nucleosides and razoxane, and via liposomal carriage and alternative methods of administration.

Energy-dependent reduced drug binding as a mechanism of Vinca alkaloid resistance in human leukemic lymphoblasts.

Abstract: We studied the accumulation of [3H]vinblastine (VLB) by lines of CCRF-CEM cultured human leukemic lymphoblasts that were either sensitive or resistant to the drug. Neither cell line metabolized VLB, nor selectively retained any radioactive impurities. There was an apparent "instantaneous" accumulation of VLB by cells of both lines, resulting in cell to medium ratios greater than 1.0 within 1 sec after drug addition. Experiments between 0 and 60 sec revealed that the presumed undirectional initial rate of VLB accumulation by resistant cells, termed CEM/VLB100, was about one-half that of sensitive CEM cells. In experiments carried out over 60 min, the VLB-resistant cells accumulated considerably less [3H]VLB than did the sensitive cells. Drug accumulation by both cell lines was temperature-sensitive, since incubation of cells at 4 degrees resulted in only minimal uptake beyond that observed at zero time. CEM/VLB100 cells retained less drug than did CEM cells, apparently because of a larger fraction of readily releasable VLB compared with CEM cells. The accumulation of VLB by either cell line was related in part to cellular levels of ATP. Although depletion of ATP was associated with decreased accumulation of VLB by CEM cells, it was related to enhanced drug accumulation by CEM/VLB100 cells. Restoration of ATP levels to near control values by addition of glucose also had opposite effects on the two cell lines, causing further accumulation of VLB by the sensitive line but leading to apparent drug efflux from the resistant line. Potentially competing substrates (VM-26, colchicine, daunorubicin, and doxorubicin) failed to block this glucose-mediated release of VLB from the CEM/VLB100 cells. In experiments with energy-depleted CEM/VLB100 cells preloaded with VLB and then incubated in drug-free medium, initial drug loss was shown to be independent of cellular metabolism, being roughly the same for both metabolically intact and metabolically depleted cells. Glucose (energy) was required only for subsequent release of what appeared to be a more tightly bound cell-associated fraction of VLB. Results of zero-time binding studies tended to confirm that VLB binding by resistant cells has two components, one requiring and the other not requiring metabolic energy. Differences in the proportions of these two components between the sensitive and resistant cells suggest a mechanism for resistance to VLB and similar compounds.

Adjuvant Chemotherapy with Doxorubicin (Adriamycin) and 5–Fluorouracil in T3, NX, MO Bladder Cancer Treated with Radiotherapy

Abstract: Radical radiotherapy alone has been compared with radical radiotherapy followed by chemotherapy using doxorubicin (Adriamycin) and 5-fluorouracil in a randomised prospective study on 129 patients presenting with T3, NX, MO transitional cell carcinoma of the bladder. One hundred and ten patients were evaluable with a minimum follow-up of 2 years. The addition of this form of chemotherapy did not appear to influence the survival rate or the proportion of patients free from tumour. It cannot be recommended for routine use in the primary treatment of infiltrating bladder cancer.

Isolation and Preliminary Characterization of an Adriamycin-resistant Murine Fibrosarcoma Cell Line

Abstract: A variant cell line (UV-2237-ADM R ) resistant to the anthracycline antibiotic Adriamycin (doxorubicin) was selected in vitro from the murine UV-2237 fibrosarcoma tumor cell line. Resistance to Adriamycin proved to be a stable characteristic of the UV-2237-ADM R line, whether the line was grown in vivo or in vitro . The UV-2237-ADM R line also exhibited increased resistance to N -trifluoroacetyladriamycin-14-valerate, daunorubicin, actinomycin D, amsacrine, mitomycin C, vinblastine, and vincristine but not to bleomycin. Cell-cell hybridization studies showed that the Adriamycin resistance is an incompletely dominant trait. Uptake and efflux studies with [ 14 C]Adriamycin indicated that the resistance exhibited by the UV-2237-ADM R line was due to both reduced uptake of the drug and an increased active efflux.

CAP (cyclophosphamide, doxorubicin, and cisplatin) regimen in adrenal cortical carcinoma.

Abstract: Eleven patients with advanced progressive metastatic adrenal cortical carcinoma, for whom no further standard therapy was available, were entered into a phase II study of cyclophosphamide, doxorubicin, and cisplatin (CAP) combination chemotherapy. Two partial responses and six disease stabilizations were observed. Patients with partial responses survived 18+ and 23 months; the median survival of patients with disease stabilization was 10+ months. The total group had a median survival of 10+ months. These results, together with the modest toxicity, suggest that further study of the combination is warranted.

Scalp hypothermia: a comparison of ice packs and the Kold Kap in the prevention of doxorubicin-induced alopecia.

Abstract: Two methods of scalp hypothermia were compared in preventing alopecia, a side effect of doxorubicin chemotherapy that has a significant psychologic impact on the patient. Thirty-three patients received scalp ice packs consisting of crushed ice in plastic bags. Twenty-nine patients received Kold Kap, a device that produces chilling via an endothermic reaction. Scalp hypothermia was applied for 5-10 min before the doxorubicin bolus and left in place for 30-40 min afterward. The percent of hair loss was rated at each visit and photographs were used to further quantitate any hair loss. Sixty-three percent of Kold Kap and 56% of ice pack patients had good or better protection and did not require wigs. Excellent protection (less than 25% loss) was provided for 51% of Kold Kap and 33% of ice pack patients. Similar protection was provided to Kold Kap patients regardless of dose, while ice pack patients received significantly better protection if their doxorubicin doses were less than 50 mg. Scalp hypothermia is an effective method of preventing doxorubicin-induced alopecia.

Hyperthermic potentiation of doxorubicin and 4'-epi-doxorubicin in a transplantable neurogenic rat tumor (BT4A) in BD IX rats.

Abstract: The combined effect of hyperthermis and doxorubicin on the neurogenic rat cell line BT 4 C was found to be synergistic in vitro . The present investigation was initiated to study if this synergistic effect also could be obtained in vivo . An enhanced effect occurred when doxorubicin and 4′-epi-doxorubicin 7 mg/kg body weight were given 30 minutes prior to local water bath hypertbermia (one hour at 44.0 °C). The local side effects of the combined treatment did not increase above that of bypertbermia alone. Therefore, local byperthermia may become a useful modality for enhancement of the effect of anthracyclines on tumors with marginal drug sensitivity or bulky tumors with poor drug penetration.

Doxorubicin (Adriamycin) transport in Ehrlich ascites tumour cells: comparison with transport in human red blood cells.

Abstract: The doxorubicin (Adriamycin) transport was investigated in murine Ehrlich ascites tumour cells by measuring the initial rate of cellular net uptake in vitro at 37°C (pH 7.3). Transport characteristics were compared with previously published data on doxorubicin transport in human red blood cells. The apparent permeability coefficient in ascites cells (2.4 × 10−5 cm sec−1) and in red cells was of the same order of magnitude when calculated from the initial influx into cells suspended in a salt solution (37°C, pH 7.3). Doxorubicin was strongly adsorbed to the cell surface of ascites cells in contrast to the doxorubicin adsorption to red cells when the cells were suspended in a salt solution. The adsorbed doxorubicin could be removed by washing the ascites cells either with DNA or with human albumin salt solutions indicating that the adsorption to cell surface components was reversible. Cell membrane modifiers, 1-alcohols, local anaesthetics, phloretin, HgCl2, para-chloromercuribenzoate, affected doxorubicin ...

Enhancement of doxorubicin and vinblastine sensitivity in anthracycline-resistant P388 cells.

Abstract: Acquired resistance to doxorubicin in a P388 murine leukemia cell subline was found to be associated with decreased drug accumulation in these cells. We have previously shown that the lipid domain of the plasma membrane in drug-resistant cells is structurally more ordered and has a lower phosphatidylcholine/sphingomyelin ratio. Perhexiline maleate and triparanol both markedly enhance the sensitivity of drug-resistant cells to doxorubicin and vinblastine but do not have an effect on anthracycline-sensitive cells. This enhanced sensitivity is associated with increased drug accumulation. Although perhexiline maleate has been reported to be a calcium antagonist in other systems, our data do not implicate this mechanism in the enhancement of cell sensitivity to doxorubicin. We suggest that this effect might be related to alterations of the cell membrane lipid domain induced by perhexiline maleate and triparanol, which result in decreased structural order of plasma membrane lipids and permit increased drug accumulation.

Synthesis, antitumor activity, and cardiac toxicity of new 4-demethoxyanthracyclines.

Abstract: The new anthracycline glycosides 4-demethoxy-4'-deoxydaunorubicin and 4-demethoxy-4'-O-methyldaunorubicin, synthesized by coupling 4-demethoxydaunomycinone with 1-chloro-derivatives of protected 4-O-methyl and 4-deoxydaunosamine derivatives, have been converted into the corresponding doxorubicin analogs. The new compounds have been compared for antitumor effect with the parent drugs and with the previously described 4-demethoxydaunorubicin, 4-demethoxy-4'-epidaunorubicin, and their doxorubicin analogs. All of the new analogs were more cytotoxic against HeLa cells in vitro and were more toxic and more potent in mice than the parent drugs. Comparison at optimal antitumor doses showed that the new analogs were as active as the parent drugs against ascitic P388 leukemia and disseminated Gross leukemia. They were also active when administered orally. The new doxorubicin analogs were slightly more active than doxorubicin against ascitic L1210 leukemia and were markedly more active against disseminated L1210 leukemia. In a parallel activity-cardiotoxicity test in C3H mice repeatedly treated iv, 4-demethoxydoxorubicin, 4-demethoxy-4'-epidoxorubicin, 4-demethoxy-4'-O-methyldoxorubicin, and 4-demethoxy-4'-deoxydoxorubicin showed antitumor activity against mammary carcinoma without inducing the typical myocardial lesions observed after doxorubicin treatment, 4-Demethoxy-4'-O-methyldoxorubicin, because of its high antitumor effectiveness, lack of cardiac toxicity in mice, and activity by the oral route, deserves further study.

Combination chemotherapy of metastatic thyroid cancer. Phase II study.

Abstract: Eleven patients with metastatic thyroid cancer received combination chemotherapy with doxorubicin, bleomycin, vincristine, and melphalan. Six of 11 patients responded, two with a minor response, three a partial, and one with a complete response. Most responses were brief (2-3 months), but the patient with a complete response is alive and free of disease at 60+ months. Toxicity was moderate and predominantly hematologic. Thyroid carcinoma is a moderately sensitive neoplasm with occasional prolonged responses to chemotherapy.

Enhancement of rat heart microsomal lipid peroxidation following doxorubicin treatment in vivo

Abstract: Cardiac microsomes from rats injected with doxorubicin (5 mg/kg ip x 3) were susceptible to dramatically enhanced NADPH-dependent lipid peroxidation in the presence of doxorubicin in vitro (18-fold increases over control peroxidation). These results suggest that doxorubicin treatment in vivo caused biochemical alterations which predisposed cardiac microsomal membranes to attack by anthracycline free radical-generated oxyradicals.

Phase II clinical trial of 4'-epi-doxorubicin in metastatic solid tumors.

Abstract: 4′-Epi-doxorubicin, one of the analogs of doxorubicin, was shown in experimental animal tumor models to have a wide spectrum of antitumor activity. In comparison, its toxic side effects were less prominent than those of doxorubicin. Results of the first phase-I and II clinical trials in human tumors have confirmed experimental data. The aim of our study was to carry out a broad phase-II clinical trial mainly in various types of primarily chemoresistant solid tumors to obtain further information on the antitumor activity spectrum and toxicity of 4′-epi-doxorubicin. Ninety-two patients, 55 males and 37 females aged from 32 to 75 with an average age of 51 years, were available for the study. Karnofsky performance status was not less than 50. Previous chemotherapy was recorded in 33 patients. The drug was administered at doses of 40mg/m2 i.v. daily for 2 days in the first 25 patients and, in all other patients, the dosage was increased to 50 mg/m2 i.v. daily for 2 days (100 mg/m2/cycle). The overall response was registered in 18 (seven complete, 11 partial remissions) out of 92 patients (20%). Regarding tumor types, the response was observed in 2/15 lung, 4/15 stomach, 3/14 colorectal, and 5/13 breast cancers. No response was observed in 11 patients with melanoma and five with hypernephroma. Toxicity was mild (myelosuppression, gastrointestinal toxicity, cardiotoxicity) and tolerable for the patients. On the basis of these results, we could conclude that 4′-epi-doxorubicin is an active antitumorigenic agent in breast cancer and in stomach, rectal, and small-cell lung tumors. These results justify further clinical investigation of this compound especially in combination chemotherapy treatment.

Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159.

Abstract: Cardiotoxicity of doxorubicin, 2 mg/kg i.p. twice weekly in rats, was assessed by serial electrocardiography and electron microscopy. The toxic effects were markedly inhibited by ICRF-159, 50 mg/kg p.o. given 1 h before doxorubicin. The development of nephropathy characterized by proteinuria, hyperlipidemia and glomerular and tubular changes was significantly retarded, and the degenerative changes of peripheral nerves were markedly reduced. On the other hand, ICRF-159 enhanced the depressant effects of doxorubicin on bone marrow function. Doxorubicin reduced body weight gain, caused ascites, decrease in heart and thymus weight, and increase in liver and kidney weight. These changes were also inhibited or attenuated by ICRF-159 pretreatment.

Analogues of morpholinyl daunorubicin and morpholinyl doxorubicin

Abstract: A group of new daunorubicin and doxorubicin derivatives is disclosed. Included in this group are 3'-deamino-3'(3"-cyano-4"-morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives thereof which have excellent activity as antitumor agents.

The Interactions of Daunomycin Adriamycin with Nucleic Acids

Abstract: Daunomycin (NSC 82151, daunorubicin) (figure 1) and Adriamycin (NSC 123127, doxorubicin) are anthracycline anticancer antibiotics isolated from strains of Streptomyces peucetius. Both drugs are in current clinical use, the former being active mainly against acute lymphocytic leukaemia. Adriamycin has an exceptionally wide spectrum of antitumour activity (Goldin et al, 1981; Arcamone, 1981), having clinical applications in the treatment of a number of solid tumours as well as acute leukaemias. Both drugs produce severe dose-dependent cumulative cardiomyopathy in a high percentage of patients. Thus there has been continuing effort in many laboratories to develop analogues with reduced toxicity, and an improved spectrum of activity; to date well over 500 daunomycin derivatives have been examined. The supposition that DNA is the major cellular receptor for the drug’s action has provided rationalisations for many of these endeavours. (See Chapter 3 of this volume and the numerous reviews available for further information on the relationships between daunomycin modification, DNA binding and biological activity (Arcamone, 1978, 1981; Arlandini, Vigevani and Arcamone, 1980; Brown, 1978; Di Marco and Arcamone, 1975; Henry, 1976; Neidle, 1978, 1979).) This chapter is concerned with the interactions of the parent antibiotics with nucleic acids, an area which has undergone extensive development since it was last reviewed in detail (Neidle, 1978).