Urinary metabolites in congenital hyperuricosuria.

The excretion of oxypurine metabolites in urine of patients with congenital hyperuricosuria exceeds, on a creatinine basis, that observed in any previously recognized metabolic anomaly. The ratio of hypoxanthine to xanthine is from 2:1 to 3:1 and results from increased hypoxanthine excretion, in contrast to other hyperuricosuric conditions where ratios of less than one have been reported. Administration of allopurinol (a xanthine-oxidase inhibitor) reduces the excretion of uric acid but results in an equivalent increase in xanthine and hypoxanthine. These features appear to be unique to congenital hyper-uricosuria.

Study of purine metabolism in a xanthinuric female.

A case of xanthinuria is briefly described, and the results of in vivo studies with (14)C-labeled oxypurines are discussed. The data demonstrate that the rate of the turnover of uric acid is normal, despite an extremely small uric acid pool. Xanthine and hypoxanthine pools were measured and their metabolism evaluated. The bulk of the daily pool of 276 mg of xanthine, but only 6% of the 960 mg of hypoxanthine, is excreted. Thus, xanthine appears to be a metabolic end product, whereas hypoxanthine is an active intermediate. Biochemical implications of this finding are discussed.

13-cis-retinoic acid plus interferon alpha-2a: highly active systemic therapy for squamous cell carcinoma of the cervix.

BACKGROUND: Chemotherapeutic study of cervical squamous cell carcinoma has shown some positive results. Complete plus partial (overall) response rates of 15%-35% (complete response rate, less than 5%) were achieved with the use of a small number of cytotoxic single agents in patients with advanced disease. In addition, overall response rates of 60%-70% (complete response rates, 10%-20%) were achieved with cisplatin-based, multiagent regimens in patients with primary, locally advanced disease. However, the lack of clear evidence that existing chemotherapy can achieve a survival benefit, coupled with the worldwide annual deaths of hundreds of thousands of women from cervical cancer, indicates the urgent need for effective systemic therapy for this disease. PURPOSE: In view of the preclinical and clinical evidence that supports testing of the novel combination of 13-cis-retinoic acid (13-cRA) plus interferon-alpha (IFN-alpha) in cervical squamous cell carcinoma, we conducted a phase II study of this regimen in locally advanced disease. METHODS: Twenty-six patients with untreated, locally advanced squamous cell carcinoma of the cervix were treated daily for at least 2 months with oral 13-cRA (1 mg/kg) and subcutaneous recombinant human IFN alpha-2a (6 million units). In 21 patients (81%), the disease was stage II or higher. RESULTS: Thirteen patients (50%) experienced major responses (tumor regression greater than or equal to 50%) in association with resolution of symptoms; one achieved complete response, and 12 experienced partial response. Seven with partial response are improving further, four are being maintained in partial response, and one responder has relapsed during therapy. The response rate is 58% (11 of 19) in patients with stage IIB or higher disease and 66% (10 of 15) in patients with bulky disease (at least one dimension greater than or equal to 10 cm). Of the 13 non-responders, nine have stable disease and four have had disease progression during therapy. Toxicity was minimal. CONCLUSION: These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.

13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin.

BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.

Amelioration of adriamycin and daunorubicin myocardial toxicity by adenosine.

Primary cultures of rat myocardial cells were used to investigate the dose and time-dependent cellular enzyme release induced by either Adriamycin or daunorubicin, Concentrations of either anthracycline (1.8 or 18 microM) produced significant release of creatine phosphokinase and lactic dehydrogenase from myocardial cells within 24 hr of exposure without a detectable decrease in cell viability. Preincubation of the myocardial cells with varying concentrations of adenosine (10 microM to 1 mM) for 24 hr prior to the addition of anthracycline decreased or prevented drug-induced enzyme release. Other putative myocardial protectants, i.e., N-acetyl-L-cysteine, alpha-tocopherol, or carnitine, were ineffective in preventing anthracycline-induced enzyme release. Although adenosine was an effective myocardial protectant, it had no significant effect on cellular uptake of daunorubicin, nor did adenosine adversely affect the oncolytic activity of daunorubicin against L1210 leukemia cells in vitro. Anthramycin, another oncolytic agent having reported cardiotoxic effects, was also tested in the in vitro system. With this drug, however, no enzyme release was detected at less than lethal doses nor did adenosine have any protective potential against the toxicity of anthramycin. Finally, Adriamycin caused no significant lactic dehydrogenase release when incubated at 1.8 or 18 microM with H9c2 cells, a cell line having primarily skeletal muscle characteristics. This result suggests a specific toxicity of anthracyclines for myocardial but not skeletal muscle cells.

Physiological disposition of 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine in humans.

[2-14C]-2,2'-Anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine ([14C]AAFC) was given to 7 patients i.v. and to 3 patients p.o. at doses of 2 or 20 mg/kg. After i.v. administration of [14C]AAFC, 20 mg/kg, maximum plasma levels of up to 42.5 mug [14C]AAFC equivalents per ml of plasma occurred. A rapid exponential decrease of the radioactivity resulted in an initial half-line of 0.5 to 1.5 hr for the first part and a half-line of 8 to 24 hr for the second part of the curve. Most of the radioactivity was unchanged starting material. In plasma, 1-beta-D-arabinofuranosyl-5-fluorocytosine was found for only a short time and at low levels after i.v. injection. Its deamination product, 1-beta-D-arabinofuranosyl-5-fluorouracil (AFU), too, showed up in minor quantities. A small amount of 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil was also detected. Administration p.o. of the 14C-labeled drug (2 mg/kg) resulted in the slow appearance of radioactivity in plasma. It peaked at 6 to 18 hr and slowly disappeared with a half-life of 12 to 18 hr. In a fasting patient, [14C]AAFC, 20 mg/kg, administered p.o. resulted in its rapid absorption into the bloodstream and in elevated levels in plasma for 48 hr. The unchanged drug and AFU were the predominant substances identified in plasms. Radioactivity after i.v. injection was found primarily in urine; only small amounts were recovered in expired air (to 2.4%) and traces were found in feces. The predominant urinary excretions product was the unchanged drug (average, 79%). The rest was AFU (average, 12.4%), 1-beta-D-arabinofuranosyl-5-fluorocytosine (average, 3.9%), and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil (average, 1.9%). After p.o. administration of the labeled drug, the calculated absorption was 32%. Urine contained about 50% unchanged drug and 40% AFU; the remainder was composed of 1-beta-D-arabinofuranosyl-5-fluorocytosine and the deaminated anhydro compound, 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorouracil. The rate of excretion in the urine was slow. In general after both i.v. and p.o. administration, spinal fluid contained considerably less radioactivity than plasma at shor intervals after the administration. At longer intervals after i.v. and p.o. administration, spinal fluid contained comparable or even considerably higher levels of radioactivity when compared to the levels in plasma. Autopsies performed 6 to 25 days after i.v. or p.o. drug administration revealed that radioactivity remained in kidney, spleen, small intestine, liver, and lung.

Water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes as potential antitumor agents.

A series of water-soluble N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results obtained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cis-dichloro-diammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice inoculated with L1210 leukemia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were administered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against L1210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1, 5, and 9 following i.p. inoculation of B16 melanoma to B6D2F1 mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). N-Benzyl-iminodiacetato(1,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containing material. The exact chemical identity of the active component of this mixture is currently under investigation. The results obtained to date, however, suggest that the N-substituted iminodiacetato(1,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.

Ascorbato(1,2-diaminocyclohexane):platinum(II) complexes, a new series of water-soluble antitumor drugs.

Dichloro-1,2-diaminocyclohexane (DACH):platinum(II), the prototype DACH:platinum complex, had good antitumor activity, was not cross-resistant with cis-dichlorodiammineplatinum(II) (DDP), but was, unfortunately, virtually insoluble in water and was, therefore, not evaluated clinically. This paper summarizes some of the chemical and biological attributes of a series of cis-bisascorbato-DACH:platinum(II) complexes (DAP). Although the primary emphasis has been placed on the DAP complex consisting of the isomeric mixture DACH, a series of complexes using the isomers of either DACH or ascorbic acid have also been synthesized. The synthetic procedure entailed reacting the water-soluble sulfato-DACH:platinum(II) with barium ascorbate, and the water-soluble product DAP was removed from the BaSO4 precipitate by filtration. Based upon elemental analysis, all the complexes had stoichiometric composition of one DACH:one platinum and two ascorbate monoanions. High-pressure liquid chromatography of cis-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultraviolet-absorbing peaks. All the DAP complexes had significant in vitro cytotoxicity against L1210 leukemia cells (L1210/0) with 50%-inhibitory dose values ranging from 2 to 5 micrograms/ml. None of the complexes was cross-resistant with DDP when tested in vitro against L1210 cells 50-fold resistant to DDP (L1210/DDP). The cis-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL X DBA/2 F1 mice inoculated i.p. with 10(6) L1210/0 cells. When administered on Days 1, 5, and 9, the DAP-1 complex consistently produced treated:control values in excess of 200% with several long-term survivors (alive 60 days after tumor inoculation). Further, the DAP-1 complex was totally non-cross-resistant with DDP when tested in vivo against a DDP-resistant L1210 line. Toxicological investigations revealed that DAP-1 was relatively nonnephrotoxic but did cause the expected bone marrow and gastrointestinal toxicity. In summary, the DAP complexes are highly water-soluble, nonnephrotoxic platinum complexes with sufficient antitumor activity to warrant further pharmacological, biochemical, and chemical investigations.

Phase I evaluation of all-trans retinoic acid with and without ketoconazole in adults with solid tumors.

PURPOSE: All-trans retinoic acid (RA) induces accelerated plasma all-trans RA clearance, presumably via cytochrome P450 enzymes. This accelerated metabolism has been shown to be inhibited in the short term by the cytochrome P450 inhibitor ketoconazole. This study was conducted to evaluate the efficacy of ketoconazole in maintaining plasma all-trans RA levels over time. PATIENTS AND METHODS: Using a randomized crossover study design, we randomly assigned six patients to receive all-trans RA (45 mg/m2 orally twice per day for 14 days of a 21-day cycle) for cycle 1 and the same dose of all-trans RA plus ketoconazole (400 mg orally for one dose, then 200 mg orally three times per day for 14 days) for cycle 2, and seven patients to receive the same treatment in the reverse order. Plasma all-trans RA levels were measured during the initial 8-hour period after all-trans RA ingestion on days 1 and 15 of cycles 1 and 2. RESULTS: There was a marked decrease in plasma all-trans RA levels after 14 days of treatment, as measured by the area under the concentration-time curve (AUC), regardless of whether ketoconazole was given (from a baseline value of 857 to 44 ng/mL/h; P = .025) or not (from 1,355 to 308 ng/mL/h; P = .123). This lack of effect on plasma all-trans RA levels was not due to inadequate plasma ketoconazole levels. Ketoconazole administration was associated with more toxicity. No objective tumor responses were observed. CONCLUSION: Ketoconazole does not appear to maintain adequate plasma all-trans RA levels over time.

Phase I evaluation of all-trans-retinoic acid in adults with solid tumors.

PURPOSE: Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing. PATIENTS AND METHODS: Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity. RESULTS: Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated. CONCLUSION: For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.

Retinoic acid and interferon in human cancer: mechanistic and clinical studies.

Various combinations of retinoids, metabolic and synthetic derivatives of vitamin A, and interferons (IFNs) have demonstrated synergistic antiproliferative, differentiating, and antiangiogenic activity in some human hematologic and solid-tumor systems. This synergistic antitumor activity may be due to enhanced gene expression. In several cell systems, the actions of IFNs are enhanced by differentiation of cells with retinoic acid (RA). Combined RA-IFN effects have been correlated with the induction of higher levels of IFN-stimulated genes than the levels induced by either agent alone. Natural and synthetic retinoids have been found to augment the antiproliferative activity of IFNs in several squamous cell carcinoma (SCC) and breast tumor cell lines. Results of recent clinical trials indicate substantial activity of 13-cis-RA (13cRA) combined with IFN against advanced SCC of the skin and cervix, and possibly against other solid tumors. Two phase II trials have confirmed activity against locally advanced SCC of the cervix. Successful integration of this regimen with radiotherapy appears to be the most probable means of optimizing clinical outcome. Further studies are needed to determine the mechanistic details of the RA-IFN interaction.

Hemolysis induced by 6-N-hydroxylaminopurine riboside, an adenosine analogue.

6-N-Hydroxylaminopurine riboside (HAPR) was studied in man because of its therapeutic activity in several transplanted animal neoplasms. It was not cross-resistant to other antimetabolites useful in the treatment of human neoplasia. HAPR produced marked hemolytic anemia at doses far below those that might have produced any cytotoxic or therapeutic effect. There was evidence of hemolysis at total doses as low as 0.5 mg/kg given intravenously. For man, HAPR is one of the most active hemolytic drugs.

Clinical pharmacology of trimetrexate.

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.

Retinoic acid and interferon combination studies in human cancer.

Retinoic acid and interferon-alpha have limited single-agent activity in advanced cancer. Cell culture data indicate that in combination these agents have enhanced activity (modulating growth and differentiation) in a number of malignant cell types. Recent clinical work in advanced squamous cell carcinoma reports major activity with this regimen. This paper reviews the preclinical and clinical data testing retinoic acid in combination with interferons and presents recent work integrating these agents with radiotherapy in locally advanced cervical cancer.

Demonstration of Ga-67 localization in human placenta.

Gallium-67 uptake was noted in the mid-pelvic uterine area of a 19-week-pregnant female. Lateral and oblique Ga-67 scans revealed an anterior location of radioactivity that correlated with the position of the placenta as determined by ultrasonic technique.

Phase I trial of a 72-h continuous-infusion schedule of fazarabine.

Fazarabine (Ara-AC), a structural analog derived from the antitumor nucleoside cytosine arabanoside (Ara-C) and 5-azacytidine (5-AC), was studied in a phase I clinical trial. Doses ranging from 0.2 to 2.0 mg m-2 h-1 were given intravenously over 72 h every 28 days. The maximum tolerated dose (MDT) was 2.00 mg m-2 h-1. The dose-limiting toxicity was myelosuppression, with granulocytopenia being quantitatively more important than thrombocytopenia or anemia. Nonhematologic toxicity was minimal. Associated with the solvent dimethylsulfoxide (DMSO) was a bitter taste and a garlic-like odor.

Clinical and clinical pharmacologic studies of 2-amino-1,3,4-thiadiazole (A-TDA:NSC 4728).

A clinical phase I-II evaluation of 2-amino-1,3,4-thiadiazole (A-TDA) administered daily, twice a week, or weekly was undertaken, in which 71 patients were treated with a range of doses from 2 mg/m2 to 200 mg/m2. Pharmacokinetic studies employing high-performance liquid chromatography (HPLC) demonstrated a terminal (beta) serum half-life of 2.19 h. Stomatitis, dermatitis, nausea, vomiting, and lethargy were observed. No significant leukopenia or thrombocytopenia, however, was noted. A-TDA administration led to hyperuricemia, which was adequately controlled with concurrent administration of allopurinol. Antitumor responses included one partial response in a patient with large cell carcinoma of the lung and three objective responses (2 non-small cell lung and 1 squamous cell carcinoma of the esophagus). Two patients with adenocarcinoma of the lung had a marked improvement of psoriasis during A-TDA therapy. Further phase II studies in patients with cancer and trials in patients with psoriasis are recommended.

Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes.

A new series of highly lipid-soluble cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane)platinum(II) complexes were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), 195pt nuclear magnetic resonance (NMR)]. cis-bis-Neopentanoato(trans-R,R-1,2-diaminocyclohexane)platinum(II ) (NPDP), cis-bis-neodecanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II ) (NDDP), and cis-bis-n-decanoato(trans-R,R-1,2-diaminocyclohexane)-platinum(II) (DEDP) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) at a 7:3 molar ratio and tested for toxicity and antitumor activity. The entrapment efficiency of the liposomal platinum (L-Pt) complexes (L-NPDP, L-NDDP, L-DEDP) was greater than 95%, and the stability in 0.9% NaCl solution at 4 degrees C was greater than 95% at day 14 in each case. The LD50 values of L-NPDP, L-NDDP, and L-DEDP when injected i.v. were 30, 54, and 150 mg/kg, respectively. L-NPDP, L-NDDP, and L-DEDP had no significant nephrotoxicity [as evidenced by a lack of elevated blood urea nitrogen (BUN) levels]. The percentages of T/C obtained after a single i.p. injection of the optimal dose of L-NPDP, L-NDDP, and L-DEDP tested against L1210 leukemia were 175%, 187%, and 212%, respectively [160% for cisplatin (CDDP)]. When a multiple i.p. injection schedule was used (on days 1, 5, and 9), L-NPDP, L-NDDP, and L-DEDP were more active than CDDP (percentage of T/C: 312%, 312%, 277%, and 220%, respectively). When injected i.v., only L-NDDP showed significant activity against L1210 leukemia i.v. (percentage of T/C: 186%). L-NDDP and L-DEDP were markedly active against L1210 leukemia resistant to CDDP (percentage of T/C: 200% and 145% vs 112% for CDDP). L-NPDP, L-NDDP, and L-DEDP also had good activity against i.p. B16 melanoma when they were injected i.p. on days 1, 5, and 9 (percentage of T/C: 206%, 225%, and 306%, respectively). L-NDDP and L-DEDP were more effective than CDDP in inhibiting the growth of liver metastases of murine M5076 reticulosarcoma, whereas L-NPDP was not active. The results obtained to date suggest that L-NDDP is the best L-Pt-complex candidate for further developmental studies.

Phase I trial of droloxifene in patients with metastatic breast cancer.

Droloxifene (3-hydroxytamoxifen) is a new, nonsteroidal antiestrogen. In comparison with tamoxifen, it has a 10- to 64-fold higher affinity for the estrogen receptor and has shown a lower estrogenic and higher antiestrogenic effect in experimental studies. The objective of this study was to determine the toxicity (and its reversibility) of droloxifene given at different doses to patients with advanced metastatic breast cancer refractory to conventional endocrine therapy and chemotherapy. In this study, 30 patients were treated in groups of 6 at 5 different doses (20, 40, 100, 200, and 300 mg) by mouth once a day. Toxic effects included hot flashes, nausea, and fatigue and were not dose-related. Toxicity did not require any dose reduction or discontinuation of therapy. There was one episode of deep venous thrombosis and pulmonary embolism. There was no complete or partial response in this study, but four patients showed a minor response (13%). These data illustrate that this drug is well tolerated and needs to be further evaluated in phase II and III studies.

Phase I clinical trial and pharmacokinetic evaluation of 4'-0-tetrahydropyranyladriamycin (THP-adriamycin).

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with alpha, beta, and gamma half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, less than 10% of the compound was eliminated in the urine within 24 h.