Biological investigation of the platinum(II)-[∗I]iodohistamine complexes of potential synergistic anti-cancer activity

Nuclear Medicine and Biology 29 (2002) 169 –175

Biological investigation of the platinum(II)-[*I]iodohistamine complexes of potential synergistic anti-cancer activity Piotr Garnuszeka,*, Iwona Licin´skaa, Janusz S. Skierskia, Mirosława Koronkiewicza, Marek Mirowskib, Rafał Wierciochb, Aleksander P. Mazureka b

a Drug Institute, 30/34 Chełmska St., 00 –725 Warsaw, Poland Department of Pharmaceutical Biochemistry, Medical University, Ło´dz´, Poland

Received 22 June 2001; revised 18 August 2001; accepted 29 September 2001

Abstract Cisplatin chemotherapy in combination with external irradiation or with low-dose continuos internal radiotherapy produces significant supra-additive treatment effects towards several tumor cells. The purpose of our research is to develop a new class of platinum-based anticancer drugs containing moieties of synergistic potency such as platinum core and a radiotherapeutic isotope which, delivered directly to the tumorous cells by a specifically designed vectors, should produce a local enhancement of therapeutic dose. Thus, we have synthesized a new platinum-iodohistamine complex and its radioactive analogues labeled with I-125 and I-131. In the present study some biological properties of those compounds have been investigated. The in vitro screening study pointed out that non-radioactive platinum-iodohistamine complex possesses high cytostatic activity against COLO-205 cells, and moderate activity against HL-60 cell line. No cytotoxicity was observed against MOLT-4 and L-1210 cells, as well as against VERO normal cells. The biodistribution of intravenously administered radioactive platinum-[131I]-iodohistamine complex to normal rats revealed the highest accumulation in the liver (c.a. 40%ID). Intraperitoneal injections of the complex to tumor-bearing C3H mice resulted in scattering of the dose in the organs (mainly in GIT, liver, kidney). The retention of radioactive complex in neoplastic tissue was 3– 4 times higher than in normal muscular tissue, although exhibited the tendency to decrease with time post injection. The results of the present study show promising features of the newly developed platinum-iodohistamine complexes and justify prospective investigation of in vivo anticancer potency on animal models of solid tumors. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Platinum-iodohistamine complexes; Iodine-131; Cytometry; Biodistribution

1. Introduction cis-Diammine-dichloro platinum(II) (cisplatin, CDDP) is one of the most successful antineoplastic drugs applied for treatment of various solid tumors. However, in spite of its strong anticancer potency, chemotherapy with cisplatin associates many serious side effects, such as: nephrotoxicity, othotoxicity, nausea and vomiting, neuropathy, allergy, etc. Thus, almost at the same time when anticancer action of cisplatin was proved, intensive investigation of its analogues has been started. Many new platinum compounds have been synthesized, and some of them have shown almost equal anticancer potency and lower toxicity compared to cisplatin [6,28,29,44]. Recently, the multifactorial strat* Corresponding author. Tel.: ⫹48-22-7180741; fax: ⫹48-227180740. E-mail address: [email protected] (P. Garnuszek).

egy of cancer therapy is observed. It has been demonstrated both in laboratory and in clinical trials, that application of some biological response modifiers (BRMs) e.g. interleukines 1 and 2 or Interferone-1␥, enhance anticancer activity of cisplatin [3,7,27,36]. This synergy enables the reduction of cisplatin dose, diminishing the side effects. A similar increase of anticancer potency has also been observed by concomitant combination of irradiation and chemotherapeutic agents. Therefore, this combining-modality approach possesses therapeutic advantage for several types of malignant tumors [4,21,33,38,42]. Ionizing radiation interacts with tissue, thereby damaging DNA and other chemical structures. The success of radiotherapy in cancer patients largely depends on tumor radiosensitivity. Increasing the ratio between sensitivity of tumor cells versus normal cells to ionizing radiation would greatly improve cancer treatment. One of the methods of radiosensitisation of tumor cells is concomitant application

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of chemotherapeutic agents that alter DNA sensitivity to irradiation. Cisplatin, likewise other platinum-based anticancer drugs, appear to be excellent radiosensitizer [11,13]. It has been demonstrated both with external irradiation protocols and with low-dose continuos internal radiotherapy that CDDP may inhibit repair of sublethal or potentially lethal damage that resulted in a significant supra-additive treatment effects against several tumor cells [10,12,20]. Therefore, in the last few years platinum-based radiochemotherapy has become standard treatment for patients with advanced, surgically unresectable non-small-cell lung cancer (NSCLC). The combined-modality approaches show good prognosis for the treatment of unresectable malignant cancer of the head and neck [4,21], and promises also efficiency in the treatment of hepatocellular carcinoma [10]. Impressive response rates and encouraging survivals have been shown in several trials of the intensive concurrent radiochemotherapy with cisplatin and external irradiation, however, often at a price of significant toxicity [31,35,43]. The internal radionuclides therapy with its low irradiation dose rate that is delivered selectively to the target tissues has become an alternative treatment option for some unresectable malignant cancers [9,41]. Taking advantage of short range of ␤ particles, or ultrashort-path-length ␣ particles and Auger’s electrons, the specific radiopharmaceuticals produce locally efficient therapeutic dose that acts in a continuous manner. Short range radiation of the high-LET decreases the risk of normal tissue damage by irradiation, thus the toxicity of internal radionuclides therapy is much lower compared to external irradiation. The synergy of anticancer action has been demonstrated both in vitro and in vivo laboratory experiments combining cisplatin treatment with iodide-131 or 186Re-HEDP radiopharmaceutical [10, 20]. Encouraging results have been also reported using [131I]MIBG and cisplatin with combined treatment protocol for metastatic neuroblastoma [33,34], and clearly superior palliative effects have been observed in patients treated with strontium-89 and CDDP, than in those treated with strontium-89 alone [39]. Only a transient hematological toxicity was observed for these radiopharmaceuticals alone or in combination with cisplatin. Using platinum radioisotopes such as: 195mPt (4.02 d; IT; total average energies per decay: E␥ 76.3 keV, Ee- 175 keV), 193mPt (4.33 d; IT; E␥ 12.6 keV, Ee- 130 keV) and 191Pt (2.9 d; EC; E␥ 296 keV, Ee- 71.9 keV, EIB 0.48 keV) [8,16], several radioactive analogues of cisplatin, carboplatin and iproplatin have been synthesized, and their utility for the determination of pharmacokinetics of the platinum-cytostatics, or therapeutic efficacy of internal radio-chemotherapy have been extensively studied [1,2, 5,14,15,23,30,32]. For example, using cisplatin labeled with 191 Pt, Areberg et al. [2] demonstrated that radioactive cisplatin is a more effective drug than non-radioactive cisplatin in retarding tumor growth on nude mice, without adding systemic toxic effects. In other in vitro studies, potentiation of tumor cell killing by trans-diammino dichloro platinum (trans-Pt) labeled with prolific Auger electrons emitter, i.e.

195m

Pt (33 Auger-electrons per decay), has been observed by Howell et al. [23]. However, the relative biological effectiveness (RBE) of Auger emitters is highly dependent on cellular localization and subcellular distribution of the radionuclides, which are governed by the distinct chemical form. The extreme cytocidal effects of the Auger-electron emitter are manifested only when it is incorporated into the DNA of proliferating cells or placed in close proximity to it [22,25,41]. Accordingly, the strong radiotoxicity of the RBE values of 7 to 9 compared to x-rays have been observed for Auger-electrons emitter 125I (25 Auger-electrons per decay) carried by iododeoxyuridine (125IUdR), which is known to covalently bind to the DNA in the cell nucleus [24,26]. Thus, considering the RBE value of 4.8 for trans195m Pt reported by Howell et al. [23], that is relatively low in view of the large number of Auger electrons emitted by 195 Pt (33/decay), it seems evident that only a part of the platinum compound reaches to the cell nucleus, thus the rest of the energy carried by Auger electrons is ineffective. Therefore, the structure of platinum chemotherapeutic, likewise its extra and intra cellular distribution, are limiting factors for anticancer activity, while the choice of radiotoxic isotope is a consequence of these features and tumor system being treated. The purpose of our research is to develop a new class of platinum-based anticancer drugs containing the moieties of synergistic potency such as platinum core and the radiotherapeutic isotope. In accordance with the concept, a complex of therapeutic factors delivered directly to tumorous cells by a specifically designed vectors, such as biomolecules or liposomes, should produce a locally effective therapeutic dose. This may be achieved by radiosensitisation of the cells, or by inhibition of the intracellular repair mechanism. In spite of recognized anticancer activity of cisplatin and its radioactive analogues, the structure of this chemotherapeutic agent needs some modifications in order to lower the side effects of the therapy, among which nephrotoxicity is the most severe. Additionally, the utilized platinum isotopes have some disadvantages for routine clinical practice, for example: high cost of production (191Pt is obtained in a high energy accelerator), or low specific activity (195mPt, very low cross section of 194Pt for thermal neutrons), or decay to long lived isotope (193mPt decay to 193Pt, t1/2 50 y). The radioisotopes of iodine are still alternative for many clinical purposes, which is due to diversity and practical utility of the decay characteristics of the attainable isotopes i.e. 131I (8.02 d; ␤-, ␥, e-), 125I (59.4 d; EC, ␥, e-), 123I (13.2 h; EC, ␥, e-) and 124I (4.18 d; EC, ␤⫹, ␥), 126I (13.02 d; ␤-, ␤⫹, ␥, e-). Long historical experience, both from laboratory and clinical practice, and good knowledge of pharmacokinetics and radiotoxicity of the iodine isotopes are also advantages that enable better prediction of their behavior and effects in vivo. Another encouraging aspect of using iodine isotopes is possibility of their easy replacement in the platinum-iodohistamine complex, i.e. Auger-electrons emitters (125I or 123 I) by ␤--emitting 131I isotope, or even synthesis of the

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mine or radio-iodinated histamine (i.e. 131I-histamine) with carrier-added iodohistamine, according to the developed procedure [17]. The stock solutions of the platinum-iodohistamine complexes were prepared in DMF. Purity, as well as radiochemical purity of the platinum-iodohistamine complexes, were monitored by RP-HPLC method (column Luna C18 5 ␮m 4.6x150 mm Phenomenex; mobile phase 10% DMF/10% H2O/80% Acetonitrile; flow rate 0.5 ml/min, temp. 30oC), and were usually greater than 98% even after one-month storage at room temperature. The estimated specific activities of the Pt(II)-[131I]iodohistamine preparations used for biodistribution studies were in the range of 0.8 to 1.5 MBq/␮mol of Pt. For in vivo studies, the injections of platinum-[131I]iodohistamine complex were prepared in 25-percentaged DMF solution in 0.9% saline. 2.2. Flow cytometry method

Fig. 1. Chemical structure of the platinum(II)-[*I]iodohistamine complex.

complex with mixed iodine isotopes (e.g. 125I and 131I), which, utilizing two kinds of radiation, should act more versatile in killing both single cells and large tumor masses. Thus, considering the attainability of the therapeutically useful iodine radioisotopes i.e. ␤- and Auger-electrons emitters (131I, and 125I or 123I, respectively), and promising features of the histamine molecule as the in vivo isotopecarrier [18], we have synthesized new platinum(II) complexes with iodohistamine (Fig. 1) and with radioactive [125I/131I]iodohistamine [17]. Preceding the investigation of the anticancer potency of the complexes in solid tumor models in vivo, in the present stage of the study we have evaluated the in vitro cytotoxic/cytostatic effects of the “cold” platinum-iodohistamine complex, and demonstrated the biological in vivo behavior of the radioactive complex in healthy rats. Initial evaluation of target to non-target ratio has also been studied using the most available mammary tumor model in C3H mice.

2. Experimental 2.1. Chemicals Iodohistamine, as well as its radioactive analogue i.e. radioiodinated histamine, were used for the complexation of platinum(II) central ion. 131I-labeled histamine (specific activity c.a. 2–3 GBq/␮g of histamine) was prepared by chloramine-T method using the carrier free Na 131I (Radioisotope Center Polatom, Poland), and the mono-[131I]iodo-histamine derivative was isolated by RP-HPLC method [18]. The platinum-iodohistamine complexes were synthesized by heating the solution of platinum(II) tetrachloride ion with iodohista-

In vitro cytostatic/cytotoxic effects of the non-radioactive platinum-iodohistamine complex were evaluated using flow cytometry method (FCM). For screening studies, five cell lines were used: the human colon adenocarcinoma COLO-205 cells, murine leukemia L-1210, the human leukemic MOLT-4 and HL-60 cells, and the monkey kidney VERO normal cells. The initial solutions of Pt-iodohistamine complex were prepared in 30% DMF in water, and then 100 ␮l of each solution was added to 10 ml of the cell cultures giving the final concentration of the complex as follow: 0.1, 1.0 and 10 ␮M. The 30% water solution of DMF was used as the control sample. The cell cultures were incubated for 4 hours at 37oC in CO2 atmosphere. The DNA and protein contents in the cells were assessed by DAPI and sulforhodamine dyes. FCM measurements were carried on using FACS-Vantage flow cytometer, equipped with twowavelenght argon ion laser emitting UV (351 nm) and blue (488 nm) light. DAPI fluorescence was analyzed with 424 nm band-pass filter, and sulforhodamine 101 with 630 nm. As external standard, trout erythrocytes, having DNA content of 5.05⫹/-0.18 pg per nucleus, were used. At least 10,000 cells were counted for each sample [40]. 2.3. Animal studies of the Pt(II)-[131I]iodohistamine complex Biodistribution of the radioactive platinum-[131I]iodohistamine were studied in healthy Wistar rats (male, weighing 190 –250g), and in tumor-bearing mice. Tumors were grown in C3H/W female inbred mice by sterile injection of cell suspension prepared from spontaneously growing mammary tumors. The animals with tumor size c.a. 1.0 cm in diameter were used. Comparative biodistribution of reference preparation of the 131I-histamine was done in tumorbearing mice.

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Fig. 2. Influence of Pt(II)-Iodohistamine complex concentration on the cell cycle phases of COLO-205 cell line (4 hr of incubation at 35oC).

2.3.1. Procedure The platinum-[131I]histamine complex under study was administered to rats intravenously into the tail vein in a volume of 0.2 ml and dose of about 2 MBq per one animal. Biodistribution of the complex and reference 131I-histamine in tumor-bearing mice were done after intraperitoneal administration of 0.5 MBq doses in 0.1 ml injections. During the course of the experiment, the animals were housed in single cages with absorbent paper at base. At selected time, 2 and 24 hrs after dosing, the animals were anesthetized and killed, and then selected organs were taken out to determine the distribution of radioactivity. The radioactivity of blood pool, urine, and samples of weighted tissues and carcass was measured using gamma counter supplied with adapter for whole body measurement. The results were calculated as percentage of dose in organs (%ID) or percentage of dose in gram of tissue (%ID/g). The animal experiments were approved by The IVth Local Animal Ethics Committee in Warsaw (the authorisation number ZB/2/2001), and were carried out in accordance with the principles of good laboratory practice.

3. Results and discussion 3.1. In vitro cytotoxicity of platinum-iodohistamine complex The cytometric study has shown a strong cytostatic activity of the platinum-iodohistamine complex against colon

cancer cells (COLO-205 cells). Moderately weak cytotoxicity against HL-60 cell line was also observed, but almost none against other cell lines used, i.e.: L-1210, MOLT-4 and VERO cell lines. As shown on Figure 2, the platinumiodohistamine complex strongly modulates the cell cycle of colon adenocarcinoma cells, which is demonstrated by significant increase of the number of cells in G1 phase (G1block). At the same time, decrease of cells in S and G2⫹M phases occurrs, indicating some disturbance of the genome functions. In consequence, inhibition of cell proliferation, as well as induction of apoptosis, are observed. The S phase is the most radiation-resistant phase of the cell cycle, and recovery from sublethal damage is most pronounced just in this phase [37]. Thus, the observed decrease of the COLO-205 cells in this phase, and significant increase of the radiosensitive cells in G1 phase suggest possible efficiency in concomitant cell killing by the platinum complex and the ionizing radiation. 3.2. Biodistribution studies The results of biodistribution in rats (Table 1) show that 2 hrs after intravenous administration of the radioactive platinum complex, it cumulates mainly in the liver (over 40%ID), and about 15%ID is cumulated in the intestines. The concentration of the radioactive complex in the liver tissue is almost constant after 24 hrs p.i.v., whereas some clearance of the activity from other tissues is observed. In spite of almost 40 percentaged excretion of the applied dose by urinary tract after 24 hrs, the retention of the complex in

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Table 1 Biodistribution of Platinum(II)-[131I]iodohistamine complex in normal Wistar rats (mean and 1 SD, n ⫽ 6) Organ or tissue

Time after peripheral intravenous administration of the complex 2 h p.i.v.

Blood (1 ml) Heart Thyroid gland Lung Liver Spleen Kidney Stomach Intestines Muscle Urine Carcass

24 h p.i.v.

%ID

%ID/g

%ID

%ID/g

0.27 ⫾ 0.03 0.24 ⫾ 0.07 1.30 ⫾ 0.21 40.51 ⫾ 1.24 1.08 ⫾ 0.42 3.07 ⫾ 0.22 1.44 ⫾ 0.45 14.54 ⫾ 1.24

0.72 ⫾ 0.13 0.33 ⫾ 0.05 0.21 ⫾ 0.07 0.74 ⫾ 0.18 3.87 ⫾ 0.30 1.60 ⫾ 0.52 1.37 ⫾ 0.19 0.62 ⫾ 0.14 0.72 ⫾ 0.04 0.06 ⫾ 0.02

0.13 ⫾ 0.03 0.16 ⫾ 0.04 0.79 ⫾ 0.48 30.64 ⫾ 1.21 1.06 ⫾ 0.48 1.83 ⫾ 0.19 0.88 ⫾ 0.18 9.29 ⫾ 0.58

0.30 ⫾ 0.05 0.17 ⫾ 0.03 0.15 ⫾ 0.04 0.43 ⫾ 0.21 3.78 ⫾ 0.24 1.65 ⫾ 0.58 0.94 ⫾ 0.15 0.48 ⫾ 0.08 0.55 ⫾ 0.06 0.03 ⫾ 0.03

11.38 ⫾ 2.91 20.17 ⫾ 2.01

kidney is rather low, and reveals a decreasing tendency i.e.: 3.07 and 1.83%ID after 2 and 24 hrs p.i.v., respectively. The pharmacokinetics of the platinum-[131I]iodohistamine complex is quite different than that for 131I-histamine preparation, which, as a highly hydrophilic compound, is rapidly and almost completely excreted with urine within 24 hrs p.i.v., and does not show any tendency to accumulate in the liver and other organs [18]. Regarding the essential differences between the pharmacokinetics of the platinum-[131I]iodohistamine complex and the referenced 131I-histamine [18], it seems that iodohistamine in the complex is tightly bound to the Pt(II) central atom, and this ligand–metal bond remains intact also under physiologic conditions. Intraperitoneal administration of the radioactive platinum-iodohistamine complex to tumor-bearing C3H mice resulted in the highest accumulation of the applied dose in the gastrointestinal tract (c.a. 20 and 14%ID after 2 and 24 hrs, respectively), and almost 10 percentaged accumulation in liver (9.63 and 8.58%ID after 2 and 24 hrs, respectively). A high concentration of the radioactive complex in the

37.32 ⫾ 2.54 16.47 ⫾ 1.66

blood and in the majority of tissues (Table 2), seems to be the consequence of a relatively higher dose of the complex applied to the mice compared to rats, as well as a slow pharmacokinetics of uncharged platinum-iodohistamine complex. Like in rats [18], the retention of intraperitonealy administered 131I-histamine preparation in tumor-bearing C3H is insignificant (Table 2). For this compound, low activity was detected in neoplastic tissue (0.84 and 0.28%ID/g after 2 and 24 hrs, respectively), that was almost exactly at the same level of the radioisotope concentration as that detected in the normal muscular tissue. On the contrary, the accumulation of the radioactive complex in tumors (3.75 and 2.30%ID/g after 2 and 24 hrs, respectively) was 3– 4 times higher, as compared to accumulation in normal muscular tissue (0.91%ID/g). However, decrease of the activity in neoplastic tissue after 24 hours suggests a non-specific mechanism of accumulation, most probably due to higher vascularisation of the tumor and high radioactivity concentration of the radioactive platinum complex in the blood.

Table 2 Comparison of activity accumulation in soft tissues of tumour-bearing C3H/W mice 2 and 24 hrs after intraperitoneal administration of 131I-histamine preparation and platinum-[131I]iodohistamine complex (tumour diameter ca. 1.0 cm; dose: 0.5 MBq, 0.5 ␮mol Pt; mean and 1 SD of the %ID/g, n ⫽ 9) Tissue (1 g)

Blood (1 ml) Thyroid gland Lung Liver Spleen Kidney GIT Muscle Tumour Urine (%ID)

131

PtCl2-[131I]iodohistamine

I-Histamine

2 h p.i.

24 h p.i.

2 h p.i.

24 h p.i.

1.60 ⫾ 0.29 2.91 ⫾ 1.54 0.94 ⫾ 0.41 0.87 ⫾ 0.17 0.93 ⫾ 0.27 1.59 ⫾ 0.50 3.66 ⫾ 1.14 0.81 ⫾ 0.19 0.84 ⫾ 0.31 70.26 ⫾ 4.84

0.34 ⫾ 0.20 0.83 ⫾ 0.45 0.38 ⫾ 0.13 0.18 ⫾ 0.05 0.32 ⫾ 0.21 0.26 ⫾ 0.11 0.66 ⫾ 0.24 0.15 ⫾ 0.09 0.28 ⫾ 0.13 86.39 ⫾ 3.61

14.23 ⫾ 3.69 3.30 ⫾ 1.42 4.58 ⫾ 0.73 9.75 ⫾ 2.26 6.04 ⫾ 2.26 10.42 ⫾ 3.64 6.07 ⫾ 1.88 0.97 ⫾ 0.21 3.75 ⫾ 1.14 15.65 ⫾ 4.84

4.53 ⫾ 0.64 3.86 ⫾ 3.37 2.34 ⫾ 0.92 7.08 ⫾ 1.12 7.18 ⫾ 0.87 7.31 ⫾ 0.93 5.19 ⫾ 0.50 0.91 ⫾ 0.35 2.30 ⫾ 0.79 33.82 ⫾ 3.04

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4. Conclusions We have presented preliminary in vitro and in vivo biological evaluations of the newly synthesized platinum(II) complexes with iodohistamine and 131I-labeled iodohistamine. The in vitro screening study pointed out that nonradioactive complex shows high cytostatic activity against solid tumor cell line i.e. colon cancer COLO-205 cell line, and a moderate effect against acute human leukemic HL-60 cell line. Using healthy rats, the biodistribution schemes of the platinum-[131I]iodohistamine complex have been established. Generally, the pharmacokinetics of the complex, particularly its high accumulation in the liver, exhibits some similarity to that observed for cisplatin and its radioactive analogues [1,14,15,30]. We have also performed initial study of the complex uptake in tumorous tissue using the most available for us mammary tumor model in C3H mice. It has been observed that the retention of radioactive complex in the neoplastic tissue is 3– 4 times higher than in normal muscular tissue. The retention mechanism of that complex seems to be due to a higher vascularization of neoplastic tissue compared to normal muscular tissue. However, the initial qualification of the complex concentration in tumor should enable quantification of the effective therapeutic doses in the prospective investigation of in vivo anticancer potency of the complex, as well as for the investigation of anti-cancer synergy of the two active moieties of the complex i.e. platinum core and the ionizing radiation (␤of 131I, or/and Auger-electrons of 125I). The obtained data enabled first description of the complex uptake in one of solid tumors. Although, based on the results of in vitro cytometric studies, in the prospective investigation we are going to focus our interest on developing an animal model of colon cancer. The results of the present stage of the study show promising features of the newly developed platinum-[*I]iodohistamine complexes, and suggest their potential application in the therapy of solid tumors. However, a rational approach to the development of cytostatics involves the use of carrier functions that cause specific accumulation of the respective compounds in the target organs or in the target cells [41,44]. Thus, we have also commenced developing of the targeting system for the platinum-iodohistamine complexes, making use of the liposomes and some bioactive peptides. Acknowledgment

[2]

[3]

[4]

[5]

[6]

[7]

[8] [9] [10]

[11] [12]

[13] [14]

[15]

[16] [17] [18]

This work was financially supported by the Drug Institute in Warsaw and by Grant No. 4 POF 01419 from the State Committee for Scientific Research (KBN).

[19]

References

[21]

[1] J. Areberg, S. Bjorkman, L. Einarsson, B. Frankenberg, H. Lundqvist, S. Mattsson, K. Norrgren, O. Scheike, R. Wallin, Gamma camera

[20]

imaging of platinum in tumours and tissues of patients after administration of 191Pt-cisplatin, Acta Oncol. 38 (2) (1999) 221– 8. J. Areberg, J. Wennerberg, A. Johnsson, K. Norrgren, S. Mattsson, Antitumor effect of radioactive cisplatin (191Pt) on nude mice, Int. J. Radiat. Oncol. Biol. Phys. 49 (3) (2001) 827–32. M.B. Atkins, K.R. O’Boyle, J.A. Sosman, G.R. Weiss, K.A. Margolin, M.L. Ernest, K. Kappler, J.W. Mier, J.A. Sparano, R.I. Fisher, et al., Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma, J. Clin. Oncol. 12 (8) (1994) 1553– 60. J.M. Bachaud, E. Chatelut, P. Canal, N. Albin, E. Yardeni, J.M. David, E. Serrano, N. Daly-Schveitzer, Radiotherapy with concomitant continuous cisplatin infusion for unresectable tumors of the upper aerodigestive tract: results of a phase I study, Am. J. Clin. Oncol. 20 (1) (1997) 1–5. J. Baer, R. Harrison, C.A. McAuliffe, A. Zaki, H.L. Sharma, A.G. Smith, Microscale syntheses of anti-tumour platinum compounds labelled with, 191Pt, Int. J. Appl. Radiat. Isot. 36 (1985) 181– 4. P.J. Bednarski, R. Gust, T. Spruss, N. Knebel, A. Otto, M. Farbel, R. Koop, E. Holler, E. von Angerer, H. Schonenberger, Platinum compounds with estrogen receptor affinity, Cancer Treat Rev. 17 (1990) 221–31. M.N. Benchekroun, R. Parker, M. Dabholkar, E. Reed, B.K. Sinha, Effects of interleukin-1 alpha on DNA repair in human ovarian carcinoma (NIH:OVCAR-3) cells: implications in the mechanism of sensitization of cis-diamminedichloro-platinum(II), Mol. Pharm. 47 (6) (1995) 1255– 60. E. Browne, R.B. Firestone, Table of Radioactive Isotopes (Edited by V.S. Shirley) John Wiley & Sons, Inc., (1986). J.F. Chatal, C.A. Hoefnagel, Radionuclide therapy, Nuclear Medicine Sextet, The Lancet, 354 (1999) 931–35. N. Chenoufi, J.L. Raoul, G. Lescoat, P. Brissot, P. Bourguet, In vitro demonstration of synergy between radionuclide and chemotherapy, J. Nucl. Med. 39 (5) (1998) 900 –3. C.N. Coleman, A.T. Turrisi, Radiation and chemotherapy sensitizers and protectors, Crit. Rev. Oncol. Hematol. 10 (3) (1990) 225–52. J.A. Dolling, D.R. Boreham, D.L. Brown, G.P. Raaphorst, R.E. Mitchel, Cisplatin-modification of DNA repair and ionizing radiation lethality in yeast, Saccharomyces cerevisiae, Mutat. Res. 433 (2) (1999) 127–36. E.B. Douple, Platinum-radiation interactions, NCI Monogr. (6) (1988) 315–9. J.A. Dowell, A.R. Sancho, D. Anand, W. Wolf, Noninvasive measurements for studying the tumoral pharmacokinetics of platinum anticancer drugs in solid tumors, Adv. Drug Deliv. Rev. 41 (1) (2000) 111–26. C. Ewen, A. Perera, J.H. Hendry, C.A. McAuliffe, H. Sharma, B.W. Fox, An autoradiographic study of the internal localisation and retention of cisplatin, iproplatin and paraplatin, Cancer Chemother Pharmacol. 22 (3) (1988) 241–5. R.B. Firestone, Table of Radioactive Isotopes, 8th edn. (Edited by V.S. Shirley) John Wiley & Sons, Inc., 1996. P. Garnuszek, Synthesis of platinum complexes with histamine and iodohistamine, Inorg. Chim. Acta. (submitted 2001) . P. Garnuszek, Licin´ ska I., A.P. Mazurek, Evaluation of radioiodinated histamine as isotope-carrier in vivo, Nucl Med Commun, 21 (5) (2000) 459 – 68. A.A. Geldof, A. Kruit, D.W. Newling, B.J. Slotman, Synergism between cisplatin and radiotherapy in an in vitro prostate tumor cell line, Anticancer Res. 19 (1A) (1999) 505– 8. A.A. Geldof, L. de Rooij, R.T. Versteegh, D.W. Newling, G.J. Teule, Combination 186Re-HEDP and cisplatin supra-additive treatment effects in prostate cancer cells, J. Nucl. Med. 40 (4) (1999) 667–71. L.B. Harrison, A. Raben, D.G. Pfister, M. Zelefsky, E. Strong, J.P. Shah, R.H. Spiro, A. Shaha, D.H. Kraus, S.P. Schantz, E. Carper, B. Bodansky, C. White, G. Bosl, A prospective phase II trial of concomitant chemotherapy and radiotherapy with delayed accelerated

P. Garnuszek et al. / Nuclear Medicine and Biology 29 (2002) 169 –175

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

fractionation in unresectable tumors of the head and neck, Head Neck, 20 (6) (1998) 497–503. K.G. Hofer, C.R. Harris, J.M. Smith, Radiotoxicity of intracelular Ga-67, I-125, H-3. Nuclear versus cytoplasmic radiation effects in murine L1210 leukemia, Int. J. Radiat. Biol. 28 (1975) 225– 41. R.W. Howell, A.I. Kassis, S.J. Adelstein, D.V. Rao, H.A. Wright, R.N. Hamm, J.E. Turner, K.S. Sastry, Radiotoxicity of platinum195m-labeled trans-platinum (II) in mammalian cells, Radiat. Res. 140 (1) (1994) 55– 62. R.W. Howell, D.V. Rao, D-Y. Hou, V.R. Narra, K.S. Sastry, The question of relative biological effectiveness and quality factor for Auger emitters incorporated into proliferating mammalian cells, Radiat. Res. 128 (1991) 282–92. A.I. Kassis, F. Fayad, B.M. Kinsey, K.S.R. Sastry, R.A. Taube, S.J. Adelstein, Radiotoxicity of 125I in mammalian cells, Radiat. Res. 111 (1987) 305–18. A.I. Kassis, K.S.R. Sastry, S.J. Adelstein, Kinetics of uptake, retention, and radiotoxicity of 125IUdR in mammalian cells: Implications of localized energy deposition by Auger processes, Radiat. Res. 109 (1987) 78 – 89. V. Kataja, A.Yap, for The NSCLC Collaborative Study Group: Combination of cisplatin and interferon-␣2a (Roferon-A) in patients with non-small cell lung cancer (NSCLC), An Open Phase II Multicentre Study, Eur. J Cancer, 31A (1) (1995) 35– 40. J.C. Kim, M.H. Lee, S.K. Choi, Synthesis and antitumor evaluation of cis-(1,2-diaminoethane) dichloroplatinum (II) complexes linked to 5and 6-methyleneuracil and -uridine analogues, Arch. Pharm. Res. 21 (4) (1998) 465–9. T. Klenner, F. Wingen, B.K. Keppler, B. Krempien, Schma¨ hl D, Anticancer-agent-linked phosphonates with antiosteolytic and antineoplastic properties: a promising perspective in the treatment of bone-related malignancies? J. Cancer Res. Clin. Oncol. 116 (4) (1990) 341–50. R.C. Lange, R.P. Spencer, H.C. Harder, The antitumor agent cisPt(NH3)2Cl2: distribution studies and dose calculations for 193mPt and, 195mPt, J. Nucl. Med. 14 (1973) 191–195. C.J. Langer, W.J. Curran, S.M. Keller, R.B. Catalano, S. Litwin, K.B. Blankstein, N. Haas, S.N. Campli, R.L. Comis, Long-term survival results for patients with locally advanced, initially unresectable nonsmall cell lung cancer treated with aggressive concurrent chemoradiation, Cancer J. Sci. Am. 2 (2) (1996) 99. M.J. Lind, D.J. Murphy, H. Sharma, N. Tinker, A. Smith, C.A. McAuliffe, D. Crowther, Comparative intraperitoneal pharmacoki-

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] [41] [42]

[43] [44]

175

netics of three platinum analogues, Cancer Chemother. Pharmacol. 28 (4) (1991) 315–7. S. Mastrangelo, A. Tornesello, L. Diociaiuti, R. Riccardi, V. Rufini, L. Troncone, Treatment with meta-[131I]iodobenzylguanidine and cisplatin in stage IV neuroblastoma, Q. J. Nucl. Med. 39 (4 Suppl 1) (1995) 69 –71. R. Mastrangelo, A. Tornesello, R. Riccardi, A. Lasorella, S. Mastrangelo, A. Mancini, V. Rufini, L. Troncone, A new approach in the treatment of stage IV neuroblastoma using a combination of [131I]meta-iodobenzylguanidine (MIBG) and cisplatin, Eur. J. Cancer, 31A (4) (1995) 606 –11. R.O. Mirimanoff, Concurrent chemotherapy (CT) and radiotherapy (RT) in locally advanced non-small cell lung cancer (NSCLC): a review, Lung Cancer, 11 Suppl 3 (1994) S79 –99. A. Nehme, A.M. Julia, S. Jozan, C. Chevreau, R. Bugat, P. Canal, Modulation of cisplatin cytotoxicity by human recombinant interferon-␥ in human ovarian cancer cell lines, Eur. J Cancer, 30A (4) (1994) 520 –5. E.K.J. Pauwels, J.W.A. Smit, A. Slats, M. Bourguignon, F. Overbeek, Health effects of therapeutic use of 131I in hyperthyroidism, Q. J. Nucl. Med. 44 (2000) 333–9. R. Sauer, S. Birkenhake, R. Kuhn, C. Wittekind, K.M. Schrott, P. Martus, Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer, Int. J. Radiat. Oncol. Biol. Phys. 40 (1) (1998) 121–7. R. Sciuto, A. Festa, A. Tofani, R. Pasqualoni, A. Semprebene, R. Cucchi, A. Ferraironi, S. Rea, C.L. Maini, Platinum compounds as radiosensitizers in strontium-89 metabolic radiotherapy, Clin. Ther., 149 (921) (1998) 43–7. J.S. Skierski, M. Koronkiewicz, P. Grieb, Effect of FMdC on the Cell Cycle of Some Leukemia Cell Lines, Cytometry, 37 (1999) 302–7. R.P. Spencer, Seevers, Jr., A.M. Friedman, (eds.) Radionuclides in therapy. CRC Press, Inc., (1987). A.T. Turrisi, 3rd, Platinum combined with radiation therapy in small cell lung cancer: focusing like a laser beam on crucial issues, Semin. Oncol. 21 (3 Suppl 6) (1994) 36 – 42. R.H. Wheeler, S. Spencer, Cisplatin plus radiation therapy, J. Infus. Chemother. 5 (2) (1995) 61– 6. P. Workman, M. D’Incalci, W. Bursch, K.R. Harrap, R.E. Hawkins, S. Neidle, G. Powis, European School of Oncology Task Force Report, New Approaches in Cancer Pharmacology: Drug Design and Development (Part, 2). Eur. J. Cancer 30A (8) (1994) 1148 – 60.