Novel chemotherapeutic agents in clinical development.

The development of new chemotherapeutic agents for cancer treatment is pursued with the hope of finding compounds with novel chemical characteristics, unique mechanisms of action, and with improved therapeutic indexes. Seven novel agents at different stages of clinical development have been selected for review. D1694 is a thymidylate synthase inhibitor that has intriguing preclinical activity. The anthrapyrazoles consist of three analogues that are undergoing phase II testing at present. One of these agents, CI-941, has been reported to have significant clinical activity in breast cancer. Lometrexol is an inhibitor of glycinamide ribonuclide transformylase, a critical enzyme in purine biosynthesis, that is undergoing phase II testing. Taxotere, a semisynthetic analogue of taxol that stabilizes microtubules, is currently undergoing phase I testing. Gemcitabine, a fluorinated analogue of deoxycytidine that can inhibit ribonucleotide reductase and be incorporated into DNA, is undergoing phase II testing. BMY-25067 is a mitomycin C analogue that is less myelosuppressive and more active than mitomycin C in preclinical models. Topotecan, a topoisomerase I inhibitor, has been shown to cause myelosuppression as the dose-limiting toxicity in phase I testing. Although each of these agents have some unique and novel characteristics that merit their clinical testing, these agents' long-range clinical role will depend on their efficacy in randomized phase III comparative trials.     

Ectopic production of human chorionic gonadotropin: A case report

The ectopic production of the β-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the β-subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the β-subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited.     

A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma

We determined the therapeutic effect of fluorouracil (5-FU) in combination with folinic acid (FA) in patients with measurable recurrent or metastatic carcinoma of the colon or rectum by comparing it to standard 5-FU therapy in a prospective randomized controlled trial. Patients were randomized to receive either FA, 200 mg/m2/d for five consecutive days, or nothing. All patients received 5-FU, 370 mg/m2/d for five days on the first course, with subsequent dose modifications to maintain equal toxicity in the two arms. One hundred thirty patients were entered on trial and only five were excluded from the analysis because they did not meet the eligibility criteria or they refused therapy after randomization. The two treatment arms were balanced for 11 clinical characteristics. Patients were evaluated for response at the end of every two treatment courses and toxicity after every course of therapy. Median follow-up was 1.45 years. Dose-limiting toxicity was mucositis and diarrhea on this treatment schedule, although neutropenia was apparent. The response rate was 33% (21 of 63 patients) in the 5-FU and FA arm and was 7% (four of 61 patients) in the 5-FU arm (P less than .0005). Time to disease progression was significantly different in the combination arm as compared with the single-agent arm (P = .023). Overall survival was significantly longer for patients treated with 5-FU and FA as compared with those receiving 5-FU alone (P = .05). The median survival was 12.6 months for patients receiving the combination, and 9.6 months for those receiving 5-FU alone. Our results indicate that the combination of 5-FU and FA is effective treatment for patients with metastatic or recurrent carcinoma of the rectum and colon who have not received prior chemotherapy.     

Cytotoxicity of adriamycin in MGH-U1 cells grown as monolayer cultures, spheroids, and xenografts in immune-deprived mice

The cytotoxic activity of Adriamycin was examined in the MGH-U1 human bladder carcinoma line, grown as monolayer culture, as spheroids, and as xenografts in immune-deprived mice. The MGH-U1 cells grown as spheroids were much more resistant to Adriamycin (concentration of drug resulting in 37% cell survival, 4.5 micrograms/ml) than when treated as monolayer cultures (concentration of drug resulting in 37% cell survival, 0.9 microgram/ml). Adriamycin fluorescence was demonstrated only in the outer two layers of cells forming the spheroids, suggesting that limited drug penetration is an important factor in the resistance of spheroids to Adriamycin. Sequential trypsinization of spheroids 750 micron in diameter allowed us to determine the cytotoxic effects of Adriamycin in MGH-U1 cells derived from different depths of the spheroid. We found that cells near the surface of the spheroid had a survival similar to those of exponentially growing monolayer cells treated with Adriamycin. Cells located in the middle of the viable rim were more resistant to Adriamycin, and those found near the necrotic center were most resistant to Adriamycin. The effects of Adriamycin treatment on spheroid growth delay were determined also. In spite of a small cytotoxic effect on the clonogenic fraction of cells in MGH-U1 spheroids, the growth delay effect of Adriamycin in intact spheroids was marked. This observation is consistent with Adriamycin killing primarily the cells in the outer layers of the spheroid, where most of the proliferation in the spheroid occurs. In vivo treatment of MGH-U1 xenografts with Adriamycin followed by assessment of cell survival in vitro showed minimal evidence of cytotoxicity, consistent with the poor drug penetration observed in the spheroid model. These studies suggest that: (a) Adriamycin penetrates poorly into solid tissues; (b) in vitro clonogenic survival following Adriamycin exposure of a cell suspension may predict falsely for drug sensitivity to chemotherapy; (c) a small decrease in clonogenic survival can be translated into a long growth delay but, ultimately, the tumor regrows because some clonogenic cells are spared; and (d) for Adriamycin, the spheroid model more closely parallels the in vivo effects than does monolayer culture. The use of the spheroid model for the study of Adriamycin cytotoxicity gives further insight into the action of this drug in solid tumors.     

Disposition of cyclophosphamide on two consecutive cycles of treatment in patients with ovarian carcinoma

The disposition of cyclophosphamide was determined in 12 women with ovarian carcinoma receiving cyclophosphamide 500 mg/m2, doxorubicin (adriamycin) 50 mg/m2 and cisplatin 50 mg/m2 during their first and second courses of therapy. Plasma samples were obtained over 24 h following the completion of the cyclophosphamide infusion and assayed for cyclophosphamide by high performance liquid chromatography. The mean disposition of cyclophosphamide conformed to a 2-compartment model with a mean terminal half-life of 7.14 h on the first course and 8.77 h on the second course. Mean area under the plasma concentration versus time curve appeared to increase from 248.8 mg.h/l for the initial course to 282.2 mg.h/l on the second. Mean total body clearance was 2.01 l/h/m2 on the first course and 1.77 l/h/m2 on the second. Volume of distribution on the first and second courses were 15.3 l/m2 and 18.1 l/m2, respectively. These results suggested that cyclophosphamide clearance decreased when given in a bolus fashion every 3 weeks. However, inter-patient and intra-patient variability was large and the differences in the calculated parameters were not statistically significant when the individual patient data was considered. It is concluded that: 1. cyclophosphamide disposition can best be fit by a bi-exponential equation; 2. considerable intra- and interpatient variability in the concentration-time profile will be encountered; 3. cyclophosphamide disposition does not change from the first to the second course. Reasons for the wide variation are proposed.     

High-performance liquid chromatographic measurement of cyclophosphamide in serum

The analysis of cyclophosphamide [N,N-bis(2-chlorethyl)-tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine -2-oxide] by high-performance liquid chromatography using ultraviolet detection is described. The method will enable measurement of serum concentrations of cyclophosphamide over a period of approximately 24 h after a dose of 150 mg, and requires 1 ml of serum. The between-day precision of the assay at concentrations of 0.3, 1.0, and 15.0 mg/L generated coefficients of variation of 11.8, 12.2, and 7.7%, respectively. Percentages of analytical recovery of cyclophosphamide and internal standard (5-ethyl-5-p-tolylbarbituric acid) were 63 and 73%, respectively. Preliminary data providing the half-life for two patients with normal renal function are presented.