Cobalamin conjugates useful as antitumor agents

Details Cobalamin conjugates useful as antitumor agents Cobalamin conjugates useful as antitumor agents

2000-10-16

2004-10-19

Low, Christopher S. F. (Department: 1653)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C514S052000, C514S064000, C536S026410, C536S026440, C536S026600, C424S001730

Reexamination Certificate

active

06806363

ABSTRACT:

BACKGROUND OF THE INVENTION
Boron neutron capture therapy is based on the nuclear reaction that occurs when a stable isotope,
10
B, is irradiated with low energy (0.025 eV) or thermal neutrons to yield helium nuclei (&agr;-particles) and
7
Li nuclei.
The therapeutic potential of this reaction was recognized by Locher over 50 years ago (Locher, G. L. et al.,
Am. J. Roentgenol. Radium Ther
., 36 1-13 (1936)), but it was Sweet (Javid, M. et al.,
J. Clin. Invest
., 31, 603-610 (1952); Sweet, W. H.,
N. Engl. J. Med
., 245, 875-878 (195 1); Sweet, W. H. et al.,
J. Neurosurg
., 9, 200-209 (1952)), who first suggested that boron neutron capture therapy (BNCT) might be useful for the treatment of brain tumors.
Shortly thereafter, a clinical trial was initiated at the Brookhaven National Laboratory in cooperation with Sweet and others at the Massachusetts General Hospital utilizing borax as the capture agent (Farr, L. E. et al.,
Am. J. Roentgenol
., 71, 279-291 (1954); Godwin, J. T. et al.,
Cancer
(
Phila
.), 601-615 (1955)). The objective at that time was to use BNCT as an adjunct to surgery for the treatment of patients with the most highly malignant and therapeutically refractory of all brain tumors, glioblastoma multiforme.
Further trials were carried out in the early 1960s, but these failed to show any evidence of therapeutic efficacy (Farr, L. E. et al., supra; Godwin, J. T. et al., supra; Asbury, A. K. et al.,
J. Neuropathol. Exp. Neurol
., 31, 278-303 (1972)) and were associated with adverse effects in normal tissues (Asbury, A. K. et al., supra). Stimulated by the more encouraging clinical studies of Hatanaka et al. (Hatanaka, H. A.,
J. Neurol
., 209, 81-94(1975); Hatanaka, H. et al.,
Boron Neutron Capture Therapy for Tumors
, Chap. 25, pp. 349-378. Niigata, Japan: Nishimura Co., Ltd. (1986)) for the treatment of malignant gliomas and those of Mishima et al. (Mishima, Y. et al.,
Lancet
., 2, 388-289 (1989)) for melanoma, there has been renewed national and international interest in BNCT.
The theoretical advantage of BNCT is that it is a two component or binary system, consisting of
10
B and thermal neutrons, which when combined together generate high linear energy transfer (LET) radiation capable of selectively destroying tumor cells without significant damage to normal tissues. In order for BNCT to succeed a critical amount of
10
B and a sufficient number of thermal neutrons must be delivered to individual tumor cells.
Over the past few years the Department of Energy and the NIH have renewed funding for BNCT-related research, and this has supported a growing number of investigators in many different disciplines. Advances in BNCT in the areas of compound distribution and pharmacokinetics compare favorably with other emerging modalities such as photon activation therapy, photodynamic therapy, and the use of radiolabeled antibodies for cancer treatment in which physiological targeting is used.
There are a number of nuclides that have a high propensity for absorbing low energy or thermal neutrons, and this property, referred to as the neutron capture cross-section (&sgr;), is measured in barns (1 b=10
−24
cm
2
). Of the various nuclides that have high neutron capture cross-sections,
10
B is the most attractive for the following reasons: (a) it is nonradioactive and readily available, comprising approximately 20% of naturally occurring boron: (b) the particles emitted by the capture reaction [
10
B(n,&agr;)
7
Li] are largely high LET: (c) their path lengths are approximately 1 cell diameter (10-14 &mgr;m), theoretically limiting the radiation effect to those tumor cells that have taken up a sufficient amount of
10
B and simultaneously sparing normal cells and (d) the extensive chemistry of boron is such that it can be incorporated into a multitude of different chemical structures.
7
Li and &agr;-particles are the primary fission product of the neutron capture reaction with
10
B. &agr;-Particles are relatively slow and give rise to closely spaced ionizing events that consist of tracks of sharply defined columns. They have a path length of approximately 10 &mgr;m, are high LET, and destroy a wide variety of biologically active molecules including DNA, RNA, and proteins. For these reasons there is little, if any, cellular repair from &agr;-particle-induced radiation injury.
Since the
10
B(n,&agr;)
7
Li reaction will produce a significant biological effect only when there is a sufficient fluence of thermal neutrons and a critical amount of
10
B localized around, on, or within the cell, the radiation produced can be extremely localized thereby sparing normal tissue components. Thus, selectivity is simultaneously one of the advantages and disadvantages of BNCT, since it requires delivery of boron-10 to tumor cells in greater amounts than normal cells.
Ideally, boron compounds to be used for BNCT should have a high specificity for malignant cells with concomitantly low concentrations in adjacent normal tissues and blood. Since it is desirable to confine the radiation solely to these cells, an intracellular and optimally intranuclear localization of boron would be preferred.
Several boron-containing derivatives of chlorpromazine have been synthesized (Nakagawa, T. et al.,
Chem. Pharm. Bull
. (
Tokyo
), 24, 778-781 (1976); Alam, F. et al.,
Sthralenter. Onkol
., 165, 121-125 (1989)) and are being evaluated for their in vivo tumor localizing properties. p-Boronophenylalanine is another compound that is being studied as a potential capture agent for the treatment of melanoma. The rationale for its use is the avidity of melanomas for aromatic amino acids and their subsequent incorporation into melanin (Ichihashi, M. et al.,
J. Invest. Dermatol
., 78, 215-218 (1982); Mishima, Y. et al.,
Neutral Capture Therapy
, 230-236, Niigata, Japan: Nishimura Co., Ltd. (1986)).
Tumor localization has been demonstrated following I.V. administration by means of whole body autoradiography (Coderre, J. A. et al.,
Cancer Res
., 48, 6313-6316 (1988)) and in several patients with cutaneous melanoma following perilesional injection (Mishirna, Y. et al.,
Sthralenther. Onkol
., 165, 251-254 (1989)). Stimulated by Mishima's experience, a number of other boron-containing amino acids have been synthesized that potentially could be incorporated in larger amounts into proteins of malignant cells (Hall, I. H. et al.,
J. Pharm. Sci
., 68, 685-688 (1979).
Another approach to the selective targeting of boron to melanomas is based on the observation that thiouracil is preferentially incorporated into melanotic melanomas during melanogenesis (Whittacker, J. R.,
J. Biol. Chem
., 246, 6217-6226(1971)). This observation provided the impetus for the synthesis of several boron-containing thiouracils (Gabel, D.,
Clinical Aspects of Neutron Capture Therapy
, 233-241, New York: Plenum Publishing Co. (1989)), and these currently are being evaluated in animals.
Two other classes of compounds with a propensity for localizing in malignant tumors are the porphyrins and the related phthalocyanines. The biochemical basis by which these compounds achieve elevated concentration in malignant tumors is unknown, but this observation has served as the rationale for the use of hematoporphyrin derivative in the photodynamic therapy of cancer (Dougherty, T. J. et al.,
Porphyrin Photosensitization,
3-13, New York: Plenum Publishing Corp. (1981)).
The high concentration of these compounds in tumors and their intracellular localization and persistence have stimulated several groups of investigators to synthesize boronated pokphyrins (Kahi, S. B. et al.,
Neutron Capture Therap
, 61-67, Niigata, Japan: Nishimura Co., Ltd. (1986)) and phthalocyanines (Alam, F. et al,
Strahlenther. Oncol
., 165, 121-123 (1989)) as potential capture agents. Boronated porphyrins appear to be 3-4 times more effective per unit dose in cell culture than the monomeric or dimeric form of Na
2
B
12
H
11
SH (Laster, B. H. et al.,
Strahlenther. Oncol
., 165, 203-205 (1989)). Although liver concentrations of these compounds

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