Showing papers on "Doxorubicin published in 1985"

Early and delayed clinical cardiotoxicity of doxorubicin.

Abstract: Five hundred thirty-four evaluable patients with breast cancer were treated with a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide. The total planned dose of doxorubicin was 300 mg/m2 in patients with Stage II or III disease, and 450 mg/m2 in patients with isolated recurrences. The median time interval from start of adjuvant therapy to time of analysis was 68 months. Two percent had congestive heart failure associated with doxorubicin. Fifteen patients showed myocardial dysfunction attributed to either additional treatment with potentially cardiotoxic drugs for recurrent disease or other causes. The incidence of congestive heart failure was 1% in patients treated with up to 300 mg/m2, and 4% in patients who received 450 mg/m2 of doxorubicin. The median time interval from the end of doxorubicin to development of congestive heart failure was 1 month (range, 0-33 months). None of the 326 patients who have been followed 3 or more years (162 followed 5 or more years) since completion of doxorubicin therapy have developed congestive heart failure which was considered to be related from that therapy.

Multidrug (pleiotropic) resistance in doxorubicin-selected variants of the human sarcoma cell line MES-SA.

Abstract: The emergence of drug-resistant tumor cells is a major limiting factor in cancer chemotherapy. There is little information about the nature of such resistant variants among human cancer cell populations. Doxorubicin (DOX)-resistant sublines of the human sarcoma cell line MES-SA were selected by continuous in vitro exposure to DOX. Stepwise increases in DOX concentration produced variants which were 25- and 100-fold resistant to DOX. These sublines displayed marked cross-resistance to daunorubicin, dactinomycin, mitoxantrone, colchicine, vincristine, vinblastine, and etoposide and moderate resistance to mitomycin C and melphalan. Cross-resistance was not observed, however, to methotrexate, 5-fluorouracil, bleomycin, carmustine, or cisplatin. DOX resistance in these cell lines appeared to be stable despite long periods of growth in drug-free medium. Two additional marker chromosomes were identified in the 100-fold resistant variant, which indicated clonal selection during drug exposure, but no double minute chromosomes or homogeneously staining regions were noted. Doxorubicin accumulation in the DOX-resistant cells was reduced by approximately 50% compared to that of the sensitive MES-SA cells, as a result of enhanced efflux of DOX from the resistant cells. There was no evidence of appreciable DOX metabolism by either the sensitive or resistant cells. These studies demonstrate marked DOX resistance and multidrug resistance arising in a human sarcoma line during exposure to DOX. The pleiotropic nature of this resistance is similar to that described in other models. Decreased drug accumulation due to enhanced drug efflux is identified as a major mechanism of resistance in these cells, although other factors may also be involved.

Properties of Antitumor Anthracyclines and New Developments in Their Application: Cain Memorial Award Lecture

Abstract: The established efficacy of doxorubicin in the medical treatment of cancer is hampered by dose limiting side effects and lack of activity on major clinical tumors The new derivative epirubicin (4'-epidoxorubicin) is already available clinically as a better tolerated drug, with confirmed efficacy on doxorubicin responsive diseases Because of the different orientation of the 4'-hydroxyl, the compound is partially detoxified in the human body by beta-glucuronidation The other clinically studied analogue, idarubicin (4-demethoxydaunorubicin), has shown clinical activity in leukemias and in breast tumors also when given po The properties of idarubicin may be related to electronic factors and to the extensive bioconversion to 13(S)-idarubicinol New lines of investigation are introduced The first is represented by the irreversible DNA binding derivatives and is exemplified by the highly potent cyanomorpholino analogues The second is based on the finding that certain structural modifications, such as in the 6-deoxy derivatives, are accompanied by resistance to enzymic reductive deglycosidation, a reaction that converts the anthracyclines to inactive compounds in hypoxic conditions The third line of investigation deals with the very lipophilic doxorubicin analogues, among which 4'-deoxy-4'-iododoxorubicin has been selected for further preclinical development because of the extended spectrum of activity also after po administration and of the cytotoxicity exhibited on doxorubicin-resistant murine leukemia cells

Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes.

Abstract: Doxorubicin possesses high affinity for binding to cardiolipin. We have utilized these properties in preparing stable liposomes of doxorubicin and cardiolipin with a net positive charge. Doxorubicin liposomes were formed by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. These liposomes were sonicated for 90 min at 37 degrees followed by extensive dialysis against buffer. The pharmacological, toxicological, and therapeutic effects of doxorubicin entrapped in cardiolipin liposomes were compared with those of free doxorubicin in mice. At a dose of 4 mg/kg i.v., the peak cardiac concentration was achieved in 30 min following free doxorubicin administration, the value being 8.1 micrograms/g. The peak cardiac concentration with doxorubicin in cardiolipin liposomes was obtained at 5 min with a value of 2.8 micrograms/g of tissue. The cardiac concentration X time values for free doxorubicin for the 24-hr period of observation were 55.1 micrograms X hr/g, whereas it was only 7.8 micrograms X hr/g with the drug entrapped in cardiolipin liposomes. Compared to free drug, the liposomal entrapped doxorubicin significantly reduced the histopathological lesions in cardiac tissue of mice at a dose of 15 mg/kg as determined by electron microscopy. The nadir of peripheral white blood cell counts in mice with free drug, 6 mg/kg, was observed on Day 3 which was 50% of control, whereas with liposomal encapsulated drug it was reduced only 23% on Day 7. Doxorubicin in cardiolipin liposomes demonstrated enhanced chemotherapeutic potential against murine ascitic P388 leukemia with a 144% increased life span compared to 55% increased life span with free drug at a dose of 7.5 mg/kg on Days 1, 3, and 7. We conclude that doxorubicin liposomes developed in these studies possess improved therapeutic action as demonstrated by their ability to reduce the toxicity of the drug substantially.

Cisplatin and doxorubicin. An effective chemotherapy combination in the treatment of advanced basal cell and squamous carcinoma of the skin.

Abstract: Eleven patients with advanced basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin were treated with cis-diamminedichloroplatinum II (cisplatin) and doxorubicin. Seven patients had prior surgery and six of these seven had prior radiation therapy. All patients had an adequate trial of chemotherapy. One patient received a second course of chemotherapy after relapse. Responses were seen in 10 of 12 (87%) of chemotherapy courses, and 5 of 11 patients (46%) have an unmaintained complete remission lasting 2 to 31 months. Toxicity was acceptable and consisted primarily of gastrointestinal side effects. These results indicate the combination of cisplatin and doxorubicin has significant activity in both advanced BCC and SCC of the skin. In addition, a portion of patients treated with the combination achieve a long-term unmaintained disease-free state.

Superior therapeutic activity of liposome-associated adriamycin in a murine metastatic tumour model.

Abstract: We have examined the anti-tumour activity of liposome-entrapped Adriamycin in a murine metastatic tumour model produced by i.v. inoculation of J-6456 lymphoma cells and affecting predominantly the liver. Sonicated liposomes containing phosphatidylcholine, a negatively-charged phospholipid and cholesterol were used in these experiments. Liposome-entrapped Adriamycin was more effective than free Adriamycin at equivalent doses of the drug. The superior therapeutic effect of the liposome-associated drug was manifest, either with a single i.v. treatment using a dose bordering the toxicity threshold of free Adriamycin or with a multi-injection schedule using smaller doses. Based on the growth kinetics data of the J-6456 lymphoma, our results indicate that tumour cell killing was enhanced by a factor of approximately 100 using the liposome associated form of Adriamycin. Histopathologic studies in mice bearing well-established metastases of the J-6456 lymphoma in liver and spleen indicated that the extent and duration of pathologic remission were significantly improved in mice receiving the liposome-entrapped drug as compared to mice receiving free drug. No significant differences in the anti-tumour effect of liposome entrapped Adriamycin were observed replacing phosphatidylserine by phosphatidylglycerol and reducing the cholesterol:phospholipid molar ratio from 100% to 25%. In contrast to the metastatic tumour model, liposome-entrapped Adriamycin was significantly less effective than free Adriamycin on the local i.m. growth of the J-6456 tumour. Altogether the survival and histopathological data presented suggest that, with regard to a group of neoplastic conditions with a predominant pattern of liver dissemination, a substantial increase in the therapeutic index of Adriamycin can be achieved in a selective manner with the use of liposomes.

Potentiation and protection of doxorubicin cytotoxicity by cellular glutathione modulation.

Abstract: One of the proposed mechanisms of doxorubicin cytotoxicity is generation of activated oxygen species, all of which are either free radical or potentially free radical species. Glutathione is an intracellular sulfhydryl-containing tripeptide that is known to detoxify free radicals and the damage they produce. The cytotoxicity of doxorubicin was evaluated following treatment with agents that will either elevate intracellular glutathione (2-oxothiazolidine-4-carboxylate) or deplete intracellular glutathione levels correlate with doxorubicin cytotoxicity, ie, elevated glutathione provides protection and decreased glutathione levels increase cytotoxicity. These results are discussed in the context of cardiac toxicity as well as enhancing tumor cell kill with doxorubicin.

Tamoxifen-citrate counteracts the antitumor effects of cytotoxic drugs in vitro.

Abstract: Hormones and cytotoxic drugs are often combined in the treatment of patients with breast carcinoma to broaden the antitumor spectrum of the therapy. We found that, in vitro, the most commonly used endocrine agent, tamoxifen citrate, attenuates the cytotoxic potential of 5-fluorouracil (5-FU) and of doxorubicin. The effect was observed on estrogen receptor positive and on estrogen receptor negative breast tumor cells. Combinations of growth inhibitory hormones and cytotoxic drugs may therefore be counter-productive. For the treatment of hormone-independent tumors they may even be harmful since in these tumors tamoxifen exerts no independent cell kill that compensates for its modifying effect on the cytotoxicity of drugs.

Thiol-dependent DNA damage produced by anthracycline-iron complexes. The structure-activity relationships and molecular mechanisms.

Abstract: Doxorubicin (Adriamycin) and daunomycin analogs have been examined for their ability to chelate iron and catalyze the oxidative cleavage of DNA. The results show that the C-11-hydroxyl group is essential for iron binding and DNA damage. Thus, the iron complexes of doxorubicin, daunomycin, carminomycin, and 4-demethoxydaunomycin are potent redox catalysts capable of reducing molecular oxygen in the presence of physiologic concentrations of glutathione. They are also effective catalysts of hydroxyl radical formation from hydrogen peroxide. With the exception of daunomycin, generation of hydroxyl radical from hydrogen peroxide is stimulated by greater than 200% by DNA addition. Analogs that lack the C-11-hydroxyl group are relatively inefficient at oxygen reduction, hydroxyl radical formation, and DNA cleavage. The potencies of the anthracycline analogs tested in the H2O2-dependent DNA cleavage reaction correlated well with their relative cardiac toxicities.

Dissociation of Antitumor Potency from Anthracycline Cardiotoxicity in a Doxorubicin Analog

Abstract: The search for new congeners of the leading anticancer drug doxorubicin has led to an analog that is approximately 1000 times more potent, noncardiotoxic at therapeutic dose levels, and non-cross-resistant with doxorubicin. The new anthracycline, 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin (MRA-CN), is produced by incorporation of the 3' amino group of doxorubicin in a new cyanomorpholinyl ring. The marked increase in potency was observed against human ovarian and breast carcinomas in vitro; it was not accompanied by an increase in cardiotoxicity in fetal mouse heart cultures. Doxorubicin and MRA-CN both produced typical cardiac ultrastructural and biochemical changes, but at equimolar concentrations. In addition, MRA-CN was not cross-resistant with doxorubicin in a variant of the human sarcoma cell line MES-SA selected for resistance to doxorubicin. Thus antitumor efficacy was dissociated from both cardiotoxicity and cross-resistance by this modification of anthracycline structure.

Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study

Abstract: Patients with limited-stage small-cell carcinoma of the lung (SCCL) were randomly assigned to a four-drug chemotherapy program consisting of methotrexate, doxorubicin, cyclophosphamide, and CCNU (MACC) or to a regimen consisting of cyclophosphamide, CCNU, and vincristine alternated with Adriamycin (Adria Laboratories, Columbus, Ohio) and vincristine (CCV/AV). All patients received 4,500 cGy, in a split course, to the primary tumor, mediastinum, and supraclavicular lymph node drainage areas and 3,000 cGy to the whole brain. After four cycles of chemotherapy, patients were randomly assigned to chemotherapy plus methanol extractable residue of BCG (MER-BCG) or no MER-BCG. The complete response frequencies were similar for the two regimens (54% and 48%) as were the median survivals (12.0 and 11.5 months) and the two-year survival rates (15% and 17%). Immunotherapy with MER-BCG did not prolong the time to disease progression or improve survival. Women had a greater chance of achieving a complete remission independent of performance status. There was a complex interaction between sex and the chemotherapy regimens that may have important implications for the design and stratification of future trials in SCCL.

The value of adjuvant chemotherapy in the management of sarcomas in children.

Abstract: Sarcomas of childhood rank fifth in incidence of malignant tumors in children younger than 15 years Among the soft tissue sarcomas, approximately 50% are rhabdomyosarcomas The remainder represent a heterogeneous group of diverse sarcomas which are not unique to children and include fibrosarcoma, synoviosarcoma, malignant fibrous histiocytoma, malignant schwannoma, angiosarcoma, leiomyosarcoma, and others The most common bone cancers in childhood are osteosarcoma and Ewing's sarcoma Although a multidisciplinary approach utilizing surgery, irradiation, and combination chemotherapy is routinely used in management of virtually all children with solid tumors, the value of adjuvant chemotherapy in select bone and rare soft tissue sarcomas is currently being tested Multiagent chemotherapy including vincristine, dactinomycin, cyclophosphamide, and Adriamycin (doxorubicin) contribute to cure rates in 65% to 75% of children with localized rhabdomyosarcoma, Stages I to III, when combined with surgery and/or irradiation Other drugs which hold promise include platinum, DTIC, methotrexate, and VP-16 The efficacy of similar drugs in the rarer pediatric soft tissue sarcomas other than rhabdomyosarcoma and its variants requires prospective randomized trials evaluating histologic grade, tumor size, and nodal status It has been suggested that the high-grade sarcomas presenting with minimal tumor bulk are most sensitive to combined radiotherapy-chemotherapy, whereas the low-grade sarcomas are more resistant to such therapy Tumor cell heterogeneity contributes to biologic diversity and response to treatment Chemotherapy as adjuvant therapy to irradiation is currently recommended and utilized for Ewing's sarcoma with survival rates approaching 80%, and disease-free survival of approximately 75% for those with localized disease Children with widespread and metastatic disease at presentation fare less well Although multiple single agents exhibit response rates ranging from 40% to 60%, including cyclophosphamide, Adriamycin, dactinomycin, BCNU, mithramycin, and 5-fluorouracil, new and more effective agents are needed Controversy regarding the value of multiagent chemotherapy in osteosarcoma has stimulated prospective randomized trials Evaluation of local control rates as well as sites and occurrence of metastases are essential in assessing the contribution of aggressive combined modality therapy in the pediatric sarcomas Emphasis on refinement of therapy in determining the risk/benefit ratio from adjuvant chemotherapy in pediatric sarcomas is mandatory Enhancement of early local reactions is apparent when adjuvant chemotherapy is used with local radiotherapy(ABSTRACT TRUNCATED AT 400 WORDS)

Chemotherapy of metastatic sweat gland carcinoma. A retrospective review

Abstract: Sweat gland carcinoma (SGC) is a rare malignancy of the skin. though many patients with SGC die of disseminated metastases, little is known regarding the value of systemic chemotherapy for this disease. We reviewed the records of 20 patients with metastatic SGC who were treated with chemotherapy at Memorial Hospital between 1968 and 1983. A large variety of drugs were given. Although only a few patients were treated with any given regimen, metastatic SGC appears to be poorly responsive to a wide variety of chemotherapeutic regimens. Five major responses were observed in 30 chemotherapy trials performed in 17 patients with measurable/evaluable disease. No patient responded to single agent therapy alone. In this small group of patients, SGC appears to be a relatively chemotherapy resistant tumor. Larger, group-wide or inter-group trials are needed to prospectively evaluate the use of chemotherapy in this disease. Doxorubicin and cyclophosphamide, the two drugs used most commonly in those combinations where responses were seen, appear to be reasonable choices for initial treatment of patients with metastatic disease. Our review does not provide data to support the empiric use of chemotherapy in an adjuvant setting.

A randomized trial comparing mitoxantrone with doxorubicin in patients with stage IV breast cancer.

Abstract: Mitoxantrone (Novantrone®; dihydroxyanthracenedione) is an anthraquinone previously shown to be active in human breast cancer. It appears to have less toxicity than doxorubicin. Results of this phase II–III randomized cross-over trial to determine the relative efficacy and toxicity of mitoxantrone in comparison to doxorubicin, are presented. Patients with measurable, recurrent breast cancer with limited prior chemotherapy with or without radiotherapy for metastatic disease, and who had not been exposed to prior doxorubicin, were randomized to receive either mitoxantrone or doxorubicin every three weeks with crossover on progression. Response rates, duration of remission, time to treatment failure, and drug toxicity, including cardiac toxicity evaluated with serial radionuclide angiocardiography, were evaluated. Differences in the response rates for the two groups were not statistically significant. Neither time to treatment failure nor duration of response are significantly different (p>0.05). With respect to toxicity, mitoxantrone treated patients consistently exhibited a lower incidence and less severe drug toxicity as compared to their doxorubicin-treated counterparts. Cardiac toxicity was carefully monitored and thus four patients on doxorubicin have had drug related congestive heart failure, as compared to none on mitoxantrone.

Phase II study of cisplatin in advanced osteogenic sarcoma. European Organization for Research on Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

Abstract: The activity of cisplatin (CDDP) against advanced osteogenic sarcoma was evaluated in 37 of 50 patients registered by the members of the European Organization for Research on Treatment of Cancer Soft Tissue and Bone Sarcoma Group between 1979 and 1982. All patients had measurable lung metastases. Thirty-one patients (84%) had received previous chemotherapy consisting mainly of high-dose methotrexate, doxorubicin, and vincristine. CDDP (100 mg/m2) was given as a 24-hour continuous infusion every 3 weeks for a minimum of two cycles, with appropriate fluids and diuretics. In the absence of impairment of the renal function and/or myelosuppression, the dose could be escalated by 20%. The overall response rate was 19% (seven responses among 37 patients), with one complete remission for 51 weeks and six partial remissions from 12 to 26 weeks. The median number of courses of CDDP administered was three, ranging from two to 11. Of 143 courses administered, only 18 (12%) had to be modified because of toxicity. In 16% of the patients some transient impairment of the renal function was observed. CDDP adds to the limited number of chemotherapeutic agents with useful properties in osteogenic sarcoma, and CDDP-containing combination chemotherapy regimens should be actively investigated.

Clinical toxicity of 4'-epi-doxorubicin (epirubicin).

Abstract: Epirubicin is a new derivative of doxorubicin characterized by an improved spectrum of activity and a better therapeutic index. At equimolar doses and in comparative studies, epirubicin proved to induce less acute toxicity than doxorubicin, in particular less vomiting, hair loss and myelotoxicity. While giving a comparable response rate in randomized breast cancer studies, epirubicin also proved to be less cardiotoxic than doxorubicin. The reduced potential for cardiac toxicity of epirubicin versus doxorubicin has been shown both by functional assessment (radionuclide cinecardioangiography) and by histopathologic evaluation (endomyocardial biopsies) at equally myelosuppressive doses or at equal doses (equimolar). The lessened cardiotoxicity of epirubicin versus doxorubicin can be explained by the different pharmacokinetic and metabolic properties of these two agents: epirubicin has been found to have a more rapid pharmacokinetic plasma clearance and an additional metabolic pathway (unique glucuronidation).

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma.

Abstract: Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin All patients had failed prior hormonal treatment Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%) Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination) Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment Moderate renal dysfunction (creatinine value 20-30 mg/dl) occurred only in the combination arm at an incidence of 23% Time to progression and survival were similar for the two treatment groups In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population

Cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced endometrial carcinoma.

Abstract: Nine of 19 patients (47%) with widespread or recurrent endometrial carcinoma responded to chemotherapy with cisplatin, doxorubicin, and cyclophosphamide. Two complete clinical responses and seven partial responses were achieved. A "second-look" laparotomy documented the complete response in one patient. The addition of cisplatin to doxorubicin and cyclophosphamide increased toxicity without increasing the antitumor activity previously reported for the two-drug combination. Performance status had a marked influence on response, while sites of metastases, amount of residual disease, and histologic grade did not affect the response rate. A schema for the treatment of patients with endometrial carcinoma with progestins and/or cytotoxic chemotherapy is suggested.

The effectiveness of the anthracycline analog 4'-epidoxorubicin in the treatment of experimental tumors: a review.

Abstract: The current report presents the data of the Division of Cancer Treatment of the National Cancer Institute (NCI) on the antitumor activity of the anthracycline antibiotic 4′-epidoxorubicin in experimental tumor systems. Direct comparisons are made with doxorubicin in individual experiments, and the data are related to those of earlier studies in the form of a review of experimental activity, in order to assess the relative activity of 4′-epidoxorubicin and doxorubicin. The experimental test models utilized by the NCI for these studies included the leukemias P388 and L1210, B-16 melanoma, Lewis lung carcinoma, the colon tumors 26 and 38, and the mammary tumors CD8F1 and C3H16/C. The human tumors growing in xenograft in athymic mice included the models LX-1 lung tumor, CX-1 colon tumor, and MX-1 mammary tumor. Additional comparisons were made with the tumor models Gross leukemia, sarcoma 180, MSV-induced sarcoma, MS-2 tumor, and a variety of human tumors growing in athymic mice, as well as with in vivo toxicologic and in vitro cytotoxicity models. Although for 4′-epidoxorubicin there is only a minimal alteration of the configuration of the doxorubicin molecule, quantitative comparison of 4′-epidoxorubicin and doxorubicin revealed not only similarities but also differences in biological activity. Both drugs showed activity against a broad spectrum of experimental tumors, with 4′-epidoxorubicin more effective against some tumors and equally effective against others. 4′-Epidoxorubicin evidenced less toxicity than doxorubicin in both acute and chronic toxicity studies with retention of therapeutic effectiveness and showed reduced cardiotoxicity. With 4′ -epidoxorubicin there resulted a higher therapeutic index and therapeutic ratio, permitting the use of higher dosage and a greater margin of safety. The preclinical differences in therapeutic and toxicologic manifestations of 4′-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubicin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.

Treatment of advanced endometrial carcinoma with doxorubicin and cisplatin: effects on both untreated and previously treated patients.

Abstract: Sixteen patients with advanced (International Federation of Gynecology and Obstetrics stage III and IV) adenocarcinoma of the endometrium were treated with twelve 28-day cycles of doxorubicin and cisplatin. Response was achieved in 92% of patients (11 responses among 12 patients) who had received no prior chemotherapy and in 50% (two responses among four patients) of previously treated patients. Median survival was 10 months. Doxorubicin and cisplatin were readily administered on an outpatient basis with comparatively low major toxic effects, primarily hematologic, renal, and gastrointestinal. These results indicate that doxorubicin and cisplatin combination therapy is effective with acceptable toxicity in patients with advanced endometrial carcinoma.

Identification of anthracycline analogues with enhanced cytotoxicity and lack of cross-resistance to adriamycin using a series of mammalian cell lines in vitro.

Abstract: Clinical resistance to adriamycin (ADR) develops readily, and cardiotoxicity is a major dose-limiting side effect. A range of anthracycline derivatives have been synthesized recently, and a number reported to exhibit significantly reduced cardiotoxicity in experimental animals. Using NIL 8 Syrian hamster overy cells and two continuous human tumour cell lines derived from colon carcinomas we have screened a series of 11 anthracycline analogues, determining their in vitro cytotoxic effects by colony-forming assays. Five agents proved significantly more cytotoxic than ADR: dihydroxyanthraquinone (DHAQ), mitoxantrone (DHAD), 4-demethoxydaunorubicin (4-DNR), 4′-0-tetrahydropyranyl-adriamycin (THP-ADR), and 4′-deoxyadriamycin (4-ADR). We have also established in vitro a subline of the L5178Y murine lymphoma resistant to ADR and have used this model to identify derivatives with potential value for overcoming ADR resistance. We have observed three patterns of response: (i) complete cross-resistance with 4′-epiadriamycin and daunorubicin; (ii) slight cross-resistance with 4-DNR, THP-ADR, 7-con-0-methyl-nogarol and aclacinomycin A; and (iii) complete absence of cross-resistance with 4-ADr, 4′-0-methyladriamycin, DHAQ, DHAD, and methylhydroxyellipticinium. These straightforward preclinical screens thus identify three drugs which may merit clinical evaluation, since they not only show an increased level of cytotoxicity in vitro to ADR at equivalent concentrations but also overcome resistance to ADR in this murine model system.

Uterine papillary serous carcinoma. Complete response to combination chemotherapy.

Abstract: A case of metastatic uterine papillary serous carcinoma with a complete response to chemotherapy is reported. The patient presented with vaginal, pelvic, and lymph node metastases 11 months after primary surgical resection was performed. A complete response to cyclophosphamide, Adriamycin (doxorubicin), and cisplatin was achieved. In this histologic pattern of endometrial adenocarcinoma, which behaves clinically like epithelial ovarian cancer, combination chemotherapy can offer significant response and palliation.

Phase II study of a combination of mitomycin, doxorubicin and cisplatin in advanced sarcomas.

Abstract: In all 63 patients were treated monthly with a combination of mitomycin, doxorubicin, and cisplatin, and 27 (43%) experienced objective regression of their advanced sarcomas during a 3-month trial. The observed regression rate is numerically higher than any previously observed at our institution.

Combined Cytotoxicity Effect of Hyperthermia and Anthracycline Antibiotics on Human Tumor Cells

Abstract: The effects of temperature on the anthracycline antibiotics-induced cell kill of DND-1A human malignant melanoma (MM) and DND-39A Burkitt's lymphoma (BL) cell lines were studied by means of a clonogenic assay. The two cell lines differed in sensitivity when exposed to heat: The MM cells were unaffected by hyperthermia (42 degrees C), whereas BL cells were sensitive to this temperature. With the MM cells, hyperthermia potentiated the cytotoxic effects of doxorubicin (ADM), daunorubicin, mitoxantrone (DHAD), and quelamycin but did not enhance that of aclacinomycin (ACM). Conversely, the exposure of cells to the anthracycline compounds at 0 degree C resulted in almost complete disappearance of cell kill effects except with ACM; ACM retained substantial cell kill effects even at the given low temperature. For BL cells, ADM- or DHAD-induced cell lethality was also potentiated by hyperthermia; ACM produced only additive cell kill. At 0 degree C, ACM's effects virtually disappeared. These data indicate that human tumor cell lines have a substantial variety in heat sensitivity and that not every anthracycline antitumor agent is potentiated by temperature. ACM's thermoresponse is unique among anthracycline antibiotics studied. Additionally, it was shown that normothermic cell kill by ADM was not affected by hyperthermic preheating; however, preheating of appropriate duration produced important influence on subsequent hyperthermic ADM-induced cell kill.