Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin.

We conducted a trial of a murine monoclonal antimelanoma antibody-ricin A chain immunotoxin (XOMAZYME-MEL) in 22 patients with metastatic malignant melanoma. The dose of immunotoxin administered ranged from 0.01 mg/kg daily for 5 days to 1 mg/kg daily for 4 days (total dose: 3.2 to 300 mg). Side effects observed in most patients were a transient fall in serum albumin with an associated fall in serum protein, weight gain, and fluid shifts resulting in edema. In addition, patients experienced mild to moderate malaise, fatigue, myalgia, decrease in appetite, and fevers. There was a transient decrease in voltage on electrocardiograms without clinical symptoms, change in serial echocardiograms or elevation of creatine phosphokinase MB isozyme levels. Symptoms consistent with mild allergic reactions were observed in three patients. The side effects were related to the dose of immunotoxin administered and were generally transient and reversible. Encouraging clinical results were observed, even after a single course of a low dose of immunotoxin. In addition, localization of antibody and A chain to sites of metastatic disease was demonstrated by immunoperoxidase staining of biopsy specimens. Additional studies are being conducted to continue the evaluation of safety and efficacy of immunotoxin therapy for malignancy.

Phase 1 immunolymphoscintigraphy with an In-111-labeled antimelanoma monoclonal antibody.

A phase 1 study was conducted using a monoclonal antimelanoma antibody-DTPA conjugate labeled with indium-111, for immunolymphoscintigraphy in patients with metastatic melanoma. The imaging agent, labeled with 1 mCi (37 MBq) In-111, was administered as an interstitial interdigital injection to six patients scheduled to undergo lymph node dissection for suspected metastatic malignant melanoma. No adverse effects were observed in any of the patients either during or after the infusion as determined by clinical and laboratory parameters. Antibodies to the murine immunoglobulin were produced in some patients. Regional lymph nodes were visualized whether tumor-bearing or not, and light microscopic autoradiography showed In-111 activity associated with histiocytes. One of two patients harboring both tumor-bearing and tumor-free lymph nodes exhibited preferential localization in tumor-bearing nodes. The authors conclude that this study demonstrates safety of the radiopharmaceutical and that further study is needed to improve its usefulness for diagnosis of lymph node metastases.

Relationship of molecular structure to in vivo scintigraphic distribution of carbon-11-labeled compounds. 4. Carbon-11-labeled mandelonitriles, Mandelic acids, and their esters.

11C-Labeled HCN was collected in water containing carrier KCN following bombardment of 99% N2-1% H2 with 22 MeV protons. 11C-Labeled mandelonitrile and p-methoxy-, p-hydroxy-, and 3,4-dihydroxymandelonitrile were synthesized from K11CN and the corresponding benzaldehyde. The initial distribution of 11C activity of these nitriles in dogs was primarily in the region of the heart, liver, and kidneys followed by rapid redistribution to the parotids and stomach with [11C]hydroxymandelonitriles. 11C-Labeled mandelic acid and m-methyl-, o-chloro-, and p-chloromandelic acid were synthesized from the corresponding [11C]mandelonitrile. Serial scintigraphy of 11C activity of these mandelic acids in dogs showed progressive renal excretion with accumulation of activity in the bladder. 11C-Labeled ethyl and benzyl mandelate were synthesized from [11CA]mandelic acid. These esters showed initial accumulation of activity in the lungs with eventual excretion by the kidneys.

Effects of prior administration of Sn(II) complexes on in vivo distribution of 99mTc-pertechnetate.

This report evaluates the effect of prior administration of several clinically used Sn(II)-containing agents on in vivo distribution of 99mTc. Abnormal binding of 99mTc to red blood cells can occur after administration of pertechnetate to patients who have previously received tin-containing agents. Increased blood levels of tin from other causes may have similar effects.

Relationship of molecular structure to in vivo scintigraphic distribution patterns of carbon-11 labeled compounds. 3. (11C)Hydantoins.

The preparation and gamma-scintigraphic evaluation of the in vivo distribution patterns in dogs of a series of structurally related hydantoins labeled with the positron emitting, 20.4 min half-life radionuclide, carbon-11 are described. Carbon-11 labeled HCN was collected in water or aqueous Me2SO containing carrier KCN following cyclotron bombardment of 99% N2-1% H2 gas mixture with 22 MeV protons for 1 hr at 25-35 muA. Five 11C-labeled 5,5-dialkylhydantoins, three [11C]diarylhydantoins, five [11C]-5-alkyl-5-phenylhydantoins, and five [11C]spirohydantoins were prepared by heating generally under pressure, a mixture of 11C-labeled KCN, which was produced by isotopic exchange with carrier KCN, the corresponding aldehyde or ketone, and excess (NH4)2CO3 in aqueous ethanol or Me2SO solvent. The 11C-labeled hydantoins were dissolved in 1-1.5% aqueous NaOH for intravenous administration to dogs. Total synthesis time was 70-106 min and 1-59 mCi of final product was available for conducting serial in vivo imaging for up to 2 hr or more with the gamma-scintillation camera. Carbon-11 activity from all compounds showed initial blood-pool distribution with variable concentration of activity in the brain, lungs, liver, and kidney. All of the 11C-labeled diarylhydantoins, and most having one phenyl substituent, and one having a hexamethylene moiety showed initial accumulation of 11C activity in brain. Carbon-11 labeled 5,5-diphenylhydantoin (dilantin) showed the greastest qualitative accumulation of activity in the brain. Those 11C-labeled hydantoins having a carboxyl substituent showed prominent renal concentration and urinary excretion of activity. Most 11-c-labeled hydantoins showed a progressive homogenous whole body distribution of activity in all cellular tissues of the body. The relatively uniform distribution of activity in cellular tissues and slow excretion from the body support the thesis that the pharmacologic action of the hydantoins is related to physical effects on biomembranes rather than to specific chemical interactions with cell constituents.

Relationship of chemical structure and solvent to in vivo scintigraphic distribution patterns of 11C compounds. II. 11C aminonitriles.

The preparation and scintigraphic evaluation of the distribution patterns in dogs of a series of structurally related aminonitriles labeled with 11C is described. Carbon-11-HCN was collected in water containing carrier NaCN following 22 MeV proton bombardment of 99% N2 and 1% H2 gas mixture for 1 hr. Ten 11C alphaN-alkylaminophenylacetonitrile hydrochlorides and 12 11C alpha-N-arylaminoarylacetonitriles were prepared from 11C-NaCN and the corresponding Schiff base, Ar-CH=N-R(Ar). Those 11C aminonitriles that were administered intravenously in aqueous solution showed some initial accumulation of activity in the liver followed by diffuse whole-body distribution and some small accumulation in urine. Aqueous insoluble 11C aminonitriles, which were administered intravenously in ethanol, ether, or DMSO, showed variable initial partial retention of activity in the lungs with prominent accumulation of activity in liver and excretion in bile. Several of these compounds showed pronounced and rapid accumulation of activity in the brain. Such activity in the brain was largely cleared within 15 min. Concentration of activity in the cerebrospinal fluid following clearance from the brain was 30 times greater than blood and equivalent in concentration to that noted in bile 18 min after intravenous administration of 11C alpha-anilinophenylacetonitrile in ethanol. These results suggest the possible correlation of regional brain uptake of activity of certain 11C aminonitriles with regional brain perfusion. Use of these or similar materials could permit assessment of brain tissue morphology followed by scintigraphic imaging of the bulk flow characteristics of cerebrospinal fluid.