Mark A. Green

Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10

PURPOSE Adjuvant cisplatin-based chemotherapy (ACT) is now an accepted standard for completely resected stage II and III A non-small-cell lung cancer (NSCLC). Long-term follow-up is important to document persistent benefit and late toxicity. We report here updated overall survival (OS) and disease-specific survival (DSS) data. PATIENTS AND METHODS Patients with completely resected stage IB (T2N0, n = 219) or II (T1-2N1, n = 263) NSCLC were randomly assigned to receive 4 cycles of vinorelbine/cisplatin or observation. All efficacy analyses were performed on an intention-to-treat basis. Results Median follow-up was 9.3 years (range, 5.8 to 13.8; 33 lost to follow-up); there were 271 deaths in 482 randomly assigned patients. ACT continues to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). ACT resulted in significantly prolonged DSS (HR, 0.73; 95% CI, 0.55 to 0.97; P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms. CONCLUSION Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm.

Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals

A folate-receptor-targeting radiopharmaceutical, Ga(III)-deferoxamine-folate (Ga-DF-Folate), was radiolabeled with two positron-emitting isotopes of gallium, cyclotron-produced (66)Ga (9.5 hour half-life) and generator-produced (68)Ga (68 minute half-life). The [(66)Ga]Ga-DF-Folate was administered to athymic mice with folate-receptor-positive human KB cell tumor xenografts to demonstrate that microPET mouse tumor imaging is feasible with (66)Ga, despite the relatively high positron energy of this radionuclide. Using the athymic mouse KB tumor xenograft model, dual-isotope autoradiography was also performed following i.v. co-administration of [(18)F]-FDG, a marker of regional metabolic activity, and folate-receptor-targeted [(111)In]In-DTPA-Folate. The autoradiographic images of 1 mm tumor sections demonstrate the gross heterogeneity of the KB cell tumor xenograft, as well as subtle disparity in the regional accumulation of the two radiotracers.

Gallium radiopharmaceutical chemistry

There are two gallium radioisotopes, 67Ga and 68Ga, possessing nuclear properties”’ that make them attractive for use in nuclear medicine (Table 1). The first, 67Ga, is cyclotron produced and is commercially available as gallium chloride and gallium citrate. The 3.3 day half-life of this isotope allows it to be employed in studies carried out over the period of several days. The second, 68Ga, has the distinction of being one of the few short-lived positron emitting radionuclides available from a parent/daughter generator system. c2) The 275 day half-life of the parent 68Ge is long enough to avoid problems in generator delivery while the 68 min half-life of the 68Ga daughter is convenient for radiopharmaceutical synthesis and limits the radiation dose received by the patient. The Ge/Ga generator may, therefore, be the “best” source of positron emitting radiopharmaceuticals for institutions that do not have access to a cyclotron, but which wish to do patient imaging by positron emission tomography (PET).“’ Using this technique, three-dimensional reconstruction of in vivo radionuelide distribution is possible following detection and electronic collimation of the two co-linear 511 keV photons produced in the positron-electron annihilation, thus providing images that map and quantitate tissue activity levels. W) The demand for new and novel positron-emitting radiopharmaceuticals will continue to increase as more institutions acquire instrumentation for imaging by positron emission tomography (PET).

Receptor-mediated targeting of 67Ga-Deferoxamine-Folate to folate-receptor-positive human kb tumor xenografts

The radiochemical synthesis and stability of 67Ga-deferoxamine-folate ([67Ga]Ga-DF-Folate) were examined as a function of DF-Folate concentration. Optimal labeling occurred at DF-Folate concentrations > or =2.5 microg/mL. To define the possible biological significance of variations in product formulation, the biodistribution of [67Ga]Ga-DF-Folate was examined as a function of administered deferoxamine-folate dose in an athymic mouse KB tumor model. The folate-receptor-positive KB tumors were found to concentrate the 67Ga radiolabel in a dose-dependent fashion, consistent with saturable involvement of the folate receptor in mediating tumor accumulation of the radiopharmaceutical.

The folate receptor as a molecular target for tumor-selective radionuclide delivery

The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates.

Structural and spectral studies of copper(II) and nickel(II) complexes of pyruvaldehyde mixed bis{N(4)-substituted thiosemicarbazones}

Abstract Pyruvaldehyde mixed bis(thiosemicarbazones) have been prepared in which the two thiosemicarbazone moieties have different N(4)-substituents. The mixed bis(thiosemicarbazones) and their copper(II) and nickel(II) complexes have been characterized with IR, electronic, mass, 1H NMR (Ni) and EPR (Cu) spectra. Representative crystal structures have been solved of nickel(II) complexes with either a pyruvaldehyde mixed bis(thiosemicarbazone) or a bis(thiosemicarbazone) with identical N(4)-substituents acting as a tetradentate ligand. [Ni(Pu4M4DE)] has an N(4)-methylthiosemicarbazone substituent on the keto “arm” and N(4)-diethylthiosemicarbazone substituent on the aldehyde arm. [Ni(Pu4M)] contains two N(4)-methylthiosemicarbazone moieties. Both bis(thiosemicarbazones) form square-planar N2S2 complexes with nickel(II) and copper(II).

Novel gallium(III) complexes transported by MDR1 P-glycoprotein: potential PET imaging agents for probing P-glycoprotein-mediated transport activity in vivo

BACKGROUNDnMultidrug resistance (MDR) mediated by expression of MDR1 P-glycoprotein (Pgp) represents one of the best characterized barriers to chemotherapy in cancer patients. Positron emission tomography (PET) agents for analysis of Pgp-mediated drug transport activity in vivo would enable noninvasive assessment of chemotherapeutic regimens and MDR gene therapy.nnnRESULTSnCandidate Schiff-base phenolic gallium(III) complexes were synthesized from their heptadentate precursors and gallium(III)acetylacetonate. Crystal structures demonstrated a hexacoordinated central gallium with overall trans-pseudo-octahedral geometry. Radiolabeled (67)Ga-complexes were obtained in high purity and screened in drug-sensitive (Pgp(-)) and MDR (Pgp(+)) tumor cells. Compared with control, lead compound 6. demonstrated antagonist-reversible 55-fold lower accumulation in Pgp-expressing MDR cells. Futhermore, compared with wild-type control, quantitative pharmacokinetic analysis showed markedly increased penetration and retention of 6. in brain and liver tissues of mdr1a/b((-/-)) gene disrupted mice, correctly mapping Pgp-mediated transport activity at the capillary blood-brain barrier and hepatocellular biliary cannalicular surface in vivo.nnnCONCLUSIONSnThese results indicate that gallium(III) complex 6. is recognized by MDR1 Pgp as an avid transport substrate, thereby providing a useful scaffold to generate (68)Ga radiopharmaceuticals for molecular imaging of Pgp transport activity in tumors and tissues in vivo using PET.

Mechanism of immunopotentiation by aluminum-containing adjuvants elucidated by the relationship between antigen retention at the inoculation site and the immune response

The relationship between depot formation and immunopotentiation was studied by comparing the retention of antigen at the inoculation site with antibody production in rats. A model (111)In-labeled alpha casein (IDCAS) antigen was formulated into four vaccines: IDCAS adsorbed onto either aluminum hydroxide adjuvant (AH) or aluminum phosphate adjuvant (AP); non-adsorbed IDCAS with phosphate-treated AP (PTAP); and IDCAS solution. Gamma scintigraphy showed the order of retention following subcutaneous administration to be: AH adsorbed>AP adsorbed>non-adsorbed with PTAP=solution. The antibody titers followed the order: non-adsorbed with PTAP=AP adsorbed>AH adsorbed>>solution. The presence of an aluminum-containing adjuvant was essential for immunopotentiation, but retention of the antigen at the inoculation site was not required.

Synthesis and evaluation of 99mTc(CO)3-DTPA-folate as a folate-receptor-targeted radiopharmaceutical

A folate-receptor-targeted 99mTc-radiopharmaceutical, [99mTc]Tc(CO)(3)DTPA-folate, was prepared by heating [99mTc]Tc(CO)(3)(H(2)O)(3)(+) in an aqueous solution of the previously reported DTPA-folate conjugate. The radiotracer was HPLC purified (> 98% radiochemical purity) and evaluated in vitro and in vivo as an agent for targeting folate-receptor-positive cells. [99mTc]Tc(CO)(3)DTPA-folate experienced high, folate-receptor-specific uptake in human KB tumor cells. Intravenous administration of [99mTc]Tc(CO)(3)DTPA-folate to athymic mice bearing KB cell tumor xenografts resulted in 99mTc tumor uptake of 1.8 +/- 0.5 and 3.3 +/- 0.2%ID/g (n = 3) at 30 minutes and 4 hours post-injection, respectively. Tumor uptake was reduced when folic acid was co-administered with the intravenous [99mTc]Tc(CO)(3)DTPA-folate, consistent with radiopharmaceutical localization being mediated by the folate receptor.

A kit formulation for preparation of [111In]In-DTPA-folate, a folate- receptor-targeted radiopharmaceutical

A kit formulation has been developed for convenient, routine compounding of (111)In-labeled In(III)-DTPA-Folate, an investigational radiopharmaceutical for targeting tumor-associated folate receptors. The kit consists of the DTPA-Folate conjugate in sodium citrate solution, from which [(111)In]In-DTPA-Folate can be rapidly and reliably compounded by the addition of aqueous [(111)In]In(III)-chloride.