Biomedical subjects
Publications and source records attributed to P V Woolley.
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Plasma perfusion over filters containing staphylococcal protein A (SPA) was used to treat 11 patients with adenocarcinoma who developed a hemolytic uremic syndrome. Immunoperfusion resulted in complete clearance of pretreatment elevated levels of circulating immune complexes in eight of the 11 patients with normalization of complement values depressed at the start of the therapy in seven. A significant rise in platelets and erythrocyte counts was achieved in nine patients, and stabilization of progressive renal impairment was achieved in six. The response was incomplete and short lived in three patients with clinically evident tumor recurrence, whereas long-term control of the syndrome was demonstrated in seven patients in complete tumor remission (no recurrence with median follow-up of 9 months). SPA immunoperfusion appears to be an effective form of therapy for this otherwise fatal syndrome.
A combination of 5-FU (600 mg/m2 on Days 1 and 8), doxorubicin (40 mg/m2 on Day 1), and cisplatin (75 mg/m2 on Day 1) has been used for treatment of 31 patients with advanced measurable adenocarcinoma of the lung and 35 with gastric cancer. The regimen was given every 4 weeks until disease progression to patients who had not received prior chemotherapy. One complete response occurred in the lung cancer group. Ten of the gastric cancer patients (29%) had partial responses. The median duration of response was 5.5 months and the median survival in responding patients was 10.8 months. Toxicity of the regimen was moderate. We conclude that this combination offers no particular advantages over previously described treatments for these diseases.
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The toxicity of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) administered as a 24 hour infusion has been evaluated. Studies of the clinical pharmacology of the drug have also been performed in 3 patients. The limiting toxicity of the drug was acute nausea, vomiting and diarrhea that was dose dependent in its severity and duration. The maximum tolerated dose was 600 mg/m2 over 24 hours. The other major toxicity was thrombocytopenia that was maximal 7-10 days after the completion of the infusion. The drug does not exhibit renal, hepatic or central nervous system toxicity. DON achieves steady state levels during these infusions and is eliminated by first order kinetics when the infusion is completed (t1/2 alpha = 1.81 h). The principal route of excretion is renal. A starting dose of 400 mg/m2 would be acceptable for Phase II studies of this drug administered on this schedule.
We have evaluated, in a controlled study, the modification of the toxicity of a single bolus dose of 5-fluorouracil (5-FU) by allopurinol. Patients first received a single dose of 5-FU and were monitored for toxicity. If a measurable nadir in WBC or platelet count occurred, then the same dose of 5-FU was repeated with concurrent allopurinol, given for four consecutive days at an initial dose of 300 mg twice daily, starting the day before the administration of 5-FU. With this schedule, each evaluable patient received courses of 5-FU with and without allopurinol that could be compared for toxicity. Twenty patients received initial 5-FU doses of either 1,200 mg/m2 or 1,500 mg/m2 and later had the same dose repeated with allopurinol. Nineteen of these patients had a higher WBC count with allopurinol than without it. In several patients who received a further course of 5-FU with 900-mg/d allopurinol, the WBC count was yet higher than with 600-mg/d allopurinol. The myelosuppression produced by 5-FU was characterized by a decrease in granulocyte levels that was much greater than the decrease in lymphocyte levels, and the result of allopurinol treatment was to attenuate this effort on granulocytes. In a second part of the trial, the goal was to establish the maximum tolerated dose of 5-FU given with concurrent allopurinol. In this part of the study, all patients entered were given 5-FU, usually 1,200 mg/m2, with allopurinol, usually 600 mg/d for four days. Escalations of one or the other drugs were made on subsequent treatments. The data for 22 patients showed that 1,800 mg/m2 of 5-FU was well tolerated if given with 600 to 1,200 mg of allopurinol per day, and that the WBC count nadirs were no more severe than those of 1,200-mg/m2 5-FU without allopurinol. Neurotoxicity became limiting in some patients treated at these higher doses. We conclude that allopurinol given in the proper dose and schedule can diminish the granulocytopenia produced by bolus doses of 5-FU, thereby allowing a 50% increase in the maximal tolerated dose of 5-FU.
We have conducted a phase I study of the cyclic peptide echinomycin (Quinomycin A) on a schedule of administration of once every 4 weeks. Ten dose levels between 20 and 1800 micrograms/m2 were studied. Acute gastrointestinal toxicity, thrombocytopenia, and transient elevations of serum transaminases occurred at doses of greater than or equal to 1000 micrograms/m2. Gastrointestinal toxicity was severe and dose-limiting in several patients at doses of 1800 micrograms/m2. Thrombocytopenia was erratic, but generally increased with drug doses. Platelet count nadirs occurred 5-10 days after administration. Hepatic toxicity was reflected in transient elevations of serum transaminases without hyperbilirubinemia. Three patients experienced apparent anaphylactic reactions to doses of 1500 micrograms/m2. The maximum tolerated single dose of echinomycin was 1800 micrograms/m2. A starting phase II dose of 1500 micrograms/m2 is recommended.
We have evaluated the toxicity of the antitumor agent spirogermanium on a schedule of continuous intravenous administration for periods up to five days. The doses tested were between 100 mg/m2/day and 500 mg/m2/day. Peripheral vein phlebitis occurred at all dose levels and was not relieved by addition of hydrocortisone or heparin to the infusion. No phlebitis occurred when the drug was administered through a central vein. The dose limiting toxicity of spirogermanium was neurologic, notably tremors and mental confusion. These problems became progressively more severe at doses above 250 mg/m2/day. There was no discernible bone marrow, renal or hepatic toxicity. One patient developed reversible interstitial pneumonitis. The recommended Phase II dose of spirogermanium is 200 mg/m2/day for five days, with the possibility of escalation in selected patients. Because spirogermanium is more toxic to tumor cells with prolonged exposure than with intermittent exposure, this schedule could be considered for Phase II trials, particularly in diseases thought to be especially sensitive such as ovarian and prostatic carcinoma or lymphomas.
The carcinogen 1-methyl-1-nitrosourea (MNU) can cause pancreatic cancer in guinea pigs. We have examined the relative damage produced by MNU treatment on the chromatin from pancreas and liver of these animals. Thermal denaturation of chromatin from guinea pig pancreas and liver was studied following parenteral administration of MNU in several doses. Estimates of single strand breakage were also obtained by examination of the fluorescence of intercalated ethidium bromide. Oligomeric chromatin melted with a main Tm at 78 degrees C, with additional components at 48 degrees C, 55 degrees C and 65 degrees C. Repetitive treatment with MNU at several doses between 20 mg/kg and 70 mg/kg produced destabilization of pancreatic chromatin as shown by a shift from 78 degrees C to lower melting components. The liver by contrast was relatively unaffected. In addition, pancreatic chromatin showed an increase in alkali-induced strand unwinding with MNU treatment, probably due to an increase in single strand breaks, while there was no change in this regard in the liver. The data indicate that the pancreas is more susceptible to damage by MNU than the liver.
1-(2-Chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU; NSC 95466) is a lipid-soluble nitrosourea that is presently in clinical trial. We have studied the pharmacological disposition of [ethyl-14C]PCNU in mice using an i.v. drug dose of 20 mg/kg/animal. Disappearance of total radioactivity from plasma was biphasic with mean half-lives of the two exponential phases of 21.7 min and 27.4 hr, respectively. The plasma half-life of intact drug was 29 min, and levels of intact drug, as measured by thin-layer chromatography, fell below detectable levels by 4 hr. The area under the plasma concentration-time curve for intact drug was 32.72 nmol X hr/ml. Computer analysis of the data for total radioactivity (PCNU equivalents), based upon an open two-compartment model, yielded values of the pharmacokinetic parameters K12, K21, and K10 of 1.49 hr-1, 0.25 hr-1, and 0.19 hr-1, respectively. The highest peak organ level of drug was 168.9 nmol of PCNU equivalents per g tissue in the liver 1 hr after drug administration. Maximum levels in kidney, lungs, heart, and spleen were observed at 5 min, with values of 119.5, 115.4, 80.3, and 66.7 nmol of PCNU equivalents per g of tissue, respectively. A high peak drug level in brain (50.6 nmol/g) agreed with the prediction that PCNU can cross the blood-brain barrier. The levels of intact drug relative to total radioactivity at 30 min were 60% in brain, 55% in heart, and 48% in spleen. The concurrent value in liver was 7% of the total radioactivity, suggesting that metabolism or decomposition of PCNU occurs in this organ. The principal excretory route of [ethyl-14C]PCNU was urinary, with a cumulative excretion of 62% in the first 24 hr.
Twenty-three patients with advanced measurable gastric cancer were treated with FAM-chlorozotocin in an attempt to demonstrate improvement in rate and duration of response over FAM (5-fluorouracil, Adriamycin and mitomycin C). Six (26%) partial responses were recorded with a median duration of two months. FAM-chlorozotocin was well tolerated with moderate myelosuppression as the major dose-limiting toxicity; the leukocyte nadir was 3.0 X 10(3)/mm3 (range, 0.9-6.0) and the platelet nadir was 100 X 10(3)/mm3 (range, 45-100). The authors were unable to find significant differences in prognostic factors such as performance status, sites of metastatic disease, intensity of therapy to account for the discrepancy in response rates between FAM (42%) and FAM-chlorozotocin (26%).
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A woman with metastatic breast carcinoma developed acute haemolytic anaemia on two occasions following treatment with methotrexate (MTX) and 5-fluorouracil (5-FU). The direct antiglobulin test was positive. Compatible control cells were pretreated with either MTX or 5-FU and subsequently incubated with patient and control sera. Agglutination in the indirect antiglobulin test was observed only in the presence of patient serum and MTX, and did not occur following pretreatment with 5-FU, folic acid, folinic acid or triamterene. There was no evidence of complement binding to the red cell surface. A macrophage assay showed increased phagocytic uptake of MTX-treated cells in the presence of patient serum. This phagocytosis was not enhanced by the addition of complement. The antibody subclass was predominantly IgG-3. The 51Cr red cell survival of autologous MTX cells was markedly shortened, indicating rapid in vivo destruction. These studies demonstrate the occurrence of acute haemolytic anaemia due to an IgG-3 antibody that reacts with erythrocytes in the presence of methotrexate. This antibody does not fix complement, but sensitizes red blood cells to phagocytosis by macrophages.
S-2-(3-Aminopropylamino)-ethylphosphorothioic acid (WR-2721) is reported to protect normal tissues from the effects of ionizing radiation and possibly alkylating agents as well. The present trial assessed the ability of this compound to modify the clinical toxicity of cyclophosphamide. Patients with advanced cancer first received a dose of 1000 mg/m2 cyclophosphamide intravenously and were observed for toxicity, principally myelosuppression. After the nadir in white blood cell counts and/or platelets had been documented and adequate recovery had occurred, a second course of cyclophosphamide was given, this time preceded by WR-2721 30 min earlier. In this fashion, each patient served as his own control. Doses of WR-2721 ranging from 250 to 1000 mg/m2 were tested. A total of 13 evaluable courses of WR-2721 were given with cyclophosphamide. In no instance did the prior administration of WR-2721 diminish the bone marrow toxicity of cyclophosphamide alone. At the end of the trial two additional patients received the WR-2721 in a split dose, one-half prior to the cyclophosphamide and one-half 6 hr later; again there was no protection. The side effects of WR-2721 included nausea, vomiting, hypotension, sneezing, and swelling of the tongue. We conclude that WR-2721 is a potentially toxic compound that produces no amelioration of cyclophosphamide toxicity in the doses used. Because of the severity of the side effects of WR-2721, principally hypotension, the trial was terminated after 1000 mg/m2 WR-2721 failed to protect against the toxicity of 1000 mg/m2 cyclophosphamide.
Chemotherapy with 5-fluorouracil, doxorubicin, and mitomycin-C was administered to 17 patients with locally advanced pancreatic cancer. The median survival for these patients was 8 months. With a multiaxial retrospective analysis, the overall survival of this study group appears to be least equivalent to that reported with 6,000 photon rad alone or of neutrons, and compares favorably to that achieved with combined 6,000 photo rad plus 5-fluorouracil. Of 15 relapses, only 4 had presented with evidence of disseminated disease. Based upon this analysis we recommend additional studies of combination chemotherapy with radiation therapy in future prospective randomized trials.
We used mitoguazone (500 mg/m2 iv weekly, with 50-mg/m2 escalations weekly as tolerated) to treat 22 patients with squamous cell carcinoma of the head and neck which recurred after initial therapy. Nine of 22 (11%) patients responded: two had complete responses and seven had partial responses. Gastrointestinal toxicity and anemia were commonly seen. We conclude that mitoguazone is active in squamous cell carcinoma of the head and neck and should be incorporated into phase III trials.
Gastric cancer is the most chemotherapy-responsive adenocarcinoma of the major gastrointestinal sites. For patients with advanced disease, the response rates and survival achieved with recently designed Adriamycin-based regimens represent an improvement over the past use of 5-fluourouracil alone or combined with a chloroethylnitrosourea. Effective palliative treatment can be administered in an out-patient setting without the necessity of producing severe or life-threatening toxicity. Nevertheless, response durations are finite, as is patient survival. It is essential that Phase II trials of new drugs be continued in an attempt to identify agents with greater therapeutic activity for this disease. For the locally unresectable stage, combined modality therapy incorporating palliative resection of the primary tumor, regional radiation therapy and chemotherapy, has provided long-term disease-free survival for 15--25% of all patients. The most promising aspect of current clinical investigation is the application of the Adriamycin-based drug combinations in controlled trials of surgical adjuvant therapy.
We have tested methyl glyoxal bis-guanyl hydrazone (NSC 32946) for antitumor activity in patients with colorectal carcinoma and non-small cell bronchogenic carcinoma. The drug dose was 500 mg/m2 administered by single weekly injection, and with a provision dose escalation. No responses were seen in 38 evaluable patients with colorectal cancer, including 17 who had received no prior chemotherapy. Three responses were seen among 42 patients with bronchogenic carcinoma. These included one each with epidermoid carcinoma, adenocarcinoma and large cell anaplastic carcinoma. None of these responders had received prior chemotherapy. Toxicity of the drug was predominantly gastrointestinal, namely nausea, vomiting and diarrhea, and tended to increase with repeated drug doses. Neurologic symptoms of various sorts were also prominent. We conclude that methyl-G is of marginal benefit in this dose and schedule to patients with bronchogenic carcinoma.