Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

https://clincancerres.aacrjournals.org/content/clincanres/5/11/3394.full.pdf

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

High-dose cytosine arabinoside therapy for refractory leukemia

Gastrointestinal toxicity of chemotherapeutic agents

Forty-nine adult patients with acute leukemia in relapse, refractory to conventional therapy, were studied. Increasing quantities of i.v. bolus high-dose cytosine arabinoside (cytarabine) were administered using the following schedules: 3 g/m2 every 12 hrs for 4-16 consecutive doses, or 4.5 g/m2 every 12 hrs for 12 consecutive doses. Patients ages ranged 16-76 year (median: 38). Thirty-seven patients had previously received either induction or maintainance therapy with conventional doses of cytarabine. Cerebral or cerebellar dysfunction attributable to cytarabine was observed in eight patients and appeared 6-8 days (mean: 6.6) after the first dose and lasted 3-7 days (mean: 4.7). None of 12 patients receiving up to 24 g/m2 total dose of 48 g/m2 developed reversible neurologic dysfunction. Four of six patients receiving 54 g/m2 developed CNS toxicity (irreversible in two cases), a significantly greater incidence compared to toxicity in patients receiving less than or equal to 48 g/m2 total dose (P less than 0.01). CNS toxicity was dose-related since patients treated for 12 consecutive doses of 4.5 g/m2 had significantly greater CNS toxicity than 12 consecutive doses at 3 g/m2 (P less than 0.04). Systemic cytarabine doses less than 54 g/m2 can be administered with minimal CNS side-effects.

Central nervous system toxicity of high-dose systemic cytosine arabinoside

The concentration dependence of the chemical shifts of the protons H-2, H-8 and H-1′ for 2′-, 3′- and 5′-AMP2− and of the protons H-2, H-7, H-8 and H-1′ for tubercidin 5′-monophosphate (= 7-deaza-AMP2−; TuMP2−) has been measured in D2O at 27°C to elucidate the self-association of the nucleoside monophosphates (NMPs). The results are consistent with the isodesmic model of indefinite non-cooperative stacking; the association constants for all four NMPs are very similar: K∼ 2 M−1. These 1H-NMR measurements and those on the dependence of the chemical shifts on the pD of the solutions indicate that the NMP2− species exist predominately in the anti conformation Comparison of the shift data for 5′-TuMP and 5′-AMP shows that no hydrogen bonding between N-7 and -PO3H− occurs; hence, the previously observed and confirmed ‘wrongway’ chemical shift [Martin, R. B. (1985) Acc. Chem. Res 18, 32] connected with the deprotonation of the -PO3H− group most probably results from the anisotropic properties of the phosphate group which is in the anti conformation close to N-7. From the dependence between the chemical shift and the-pD of the solutions the acidity constants were calculated for the four protonated NMPs, and for adenosine and D-ribose 5′-monophosphate. The measurements also allow an estimation of the first acidity constant of H3(5′-AMP)+ (pKDD3(AMP)= 0.9 and pKHH3(AMP)= 0.4). The values for pKHH2(NMP) and pKHH(NMP) were also determined from potentiometric pH titrations in aqueous solution (I= 0.1 M, NaNO3; 25°C). The agreement of the results obtained by the two methods is excellent. The position of the phosphate group at the ribose moiety and the presence of N-7 in the base moiety influence somewhat the acid-base properties of the mentioned NMPs. Measurements with 5′-AMP in 50% (v/v) aqueous dioxane show that lowering of the solvent polarity facilitates removal of the proton from the H+(N-1) site while the -PO2−3 group becomes more basic; this increases the pH range in which the monoprotonated H(5′-AMP)− species is stable and which is now also extended into the physiological pH region. Some consequences of this observation for biological systems are indicated.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1987.tb10807.x

Self-association and protonation of adenosine 5'-monophosphate in comparison with its 2'- and 3'-analogues and tubercidin 5'-monophosphate (7-deaza-AMP).

Tubercidin with EDTA has been given a Phase I clinical trial in 45 patients. The drug was mixed with approximately 500 ml blood withdrawn from the patient, with EDTA as an anticoagulant, and after 1 hr incubation at 37°, given intravenously to the patient. The dose levels ranged from 200 to 1500 μg/kg given at weekly intervals for two doses. Toxicity to the drug was uncommon and usually not severe. Hematological toxicity was noted in six patients, renal toxicity in five patients, hepatic toxicity in two patients, and severe gastrointestinal toxicity in one patient. Objective regression of the tumor was noted in four patients. The biological effect was apparent between 4 and 12 weeks after onset of therapy and was transitory.

https://cancerres.aacrjournals.org/content/canres/30/1/79.full.pdf

Clinical studies with tubercidin administered after absorption into human erythrocytes.

Cytosine arabinoside was administered to 449 patients with a variety of solid tumors. The phase I study included doses of 0.8–3.5 mg/kg × 10 days, and a small number received 5 mg/kg daily for the fir

Donald B. Rochlin

Papers

Clinical studies with tubercidin administered after absorption into human erythrocytes.

Cytosine Arabinoside (NSC 63878) Toxicity and Antitumor Activity in Human Solid Tumors