Targeted concurrent chemoradiotherapy, by using improved microcapsules that release carboplatin in response to radiation, improves detectability by computed tomography as well as antitumor activity while reducing adverse effect in vivo.

PURPOSE: The effect of alginate-hyaluronate microcapsules that release carboplatin in response to radiation was improved by adding ascorbic acid (AA). MATERIALS AND METHODS: Four measures of the effectiveness of the microcapsules were evaluated: 1) release of carboplatin in response to radiation in vitro and in vivo; 2) detectability of their accumulation by computed tomography (CT) in vivo; 3) enhancement of antitumor effects in vivo; and 4) reduction of adverse effects in vivo. RESULTS: There were significant increases in the rupture of microcapsules by adding AA in vitro. Subcutaneously injected microcapsules around the tumor could be detected by using CT and the alteration of CT-values correlated with the accumulation of the microcapsules. Those microcapsules released carboplatin and resulted in synergistic antitumor effect with concomitant radiation. With the encapsulation of carboplatin, chemotherapeutic effects were still observed two weeks after treatment. However, addition of AA did not result in increased antitumor effect in vivo. A reduction in adverse effects was observed with the encapsulation of carboplatin, through localization of carboplatin around the tumor. CONCLUSION: Addition of AA to the materials of microcapsules did not result in increasing antitumor effect. However encapsulation of carboplatin will be useful as a clinical cancer-therapy option.

Antitumor carboplatin is more toxic in tumor cells when photoactivated: enhanced DNA binding.

Carboplatin, an analogue of "classical" cis-diamminedichloridoplatinum(II) (cisplatin), is a widely used second-generation platinum anticancer drug. Cytotoxicity of cisplatin and carboplatin is mediated by platinum-DNA adducts. Markedly higher concentrations of carboplatin are required, and the rate of adduct formation is considerably slower. The reduced toxic effects in tumor cells and a more acceptable side-effect profile are attributable to the lower reactivity of carboplatin with nucleophiles, since the cyclobutanedicarboxylate ligand is a poorer leaving group than the chlorides in cisplatin. Recently, platinum complexes were shown to be particularly attractive as potential photochemotherapeutic anticancer agents. Selective photoactivation of platinum complexes by irradiation of cancer cells may avoid enhancement of toxic side-effects, but may increase toxicity selectively in cancer cells and extend the application of photoactivatable platinum complexes to resistant cells and to a wider range of cancer types. Therefore, it was of interest to examine whether carboplatin can be affected by irradiation with light to the extent that its DNA binding and cytotoxic properties are altered. We have found that carboplatin is converted to species capable of enhanced DNA binding by UVA irradiation and consequently its toxicity in cancer cells is markedly enhanced. Recent advances in laser and fiber-optic technologies make it possible to irradiate also internal organs with light of highly defined intensity and wavelength. Thus, carboplatin is a candidate for use in photoactivated cancer chemotherapy.

[The photolytical products of aqueous carboplatin solution].

Carboplatin, an abbreviation for 1, 1-cyclobutanedicarboxylatodiamine platinum (II), is the second generation platinum anticancer drug. The stability of its aqueous solution is of great importance to clinical effects. It has been known that the solution is relatively stable with t1/2 being about three months when kept in dark place, and unstable to light as shown by the rapid change in the UV spectrum. But, the photolytic products remain unidentified. As a knowledge of the products plays an important role in understanding the influence of photolysis of carboplatin on the clinical effects, we have recently studied the photolytical products of aqueous carboplatin solution upon 313 and 254 nm irradiation, and now report our results here.

Irradiation enhances cellular uptake of carboplatin.

PURPOSE: Because radiation is known to damage cellular membranes, the purpose of this study was to determine whether irradiation of cultured cells might modify the cellular uptake of the chemotherapy agent carboplatin. METHODS AND MATERIALS: Total intracellular platinum was measured using atomic absorption spectrometry in cultured V79 cells and in four Chinese hamster ovary (CHO) cell lines. RESULTS: Intracellular carboplatin concentrations increased linearly with radiation dose (10-50 Gy) under both hypoxic and oxic irradiation conditions. Similar doses of radiation did not significantly increase the uptake of a nontoxic platinum compound [Pt(NH3)4Cl2.H2O] (p > 0.5). Compared to unirradiated controls, there was no increase in intracellular carboplatin concentrations when carboplatin was irradiated prior to administration to the cell cultures (p > 0.5). Within the 32.5 min or less required to deliver the radiation, a dose of 50 Gy produced approximately a 50% increase in intracellular platinum in V79 cells and approximately an increase of a factor of 1.3-1.6 in the CHO cell lines. Although the increase in drug uptake would be expected to be less than 10% for most cell lines at the doses of radiation used to investigate radiosensitization by carboplatin, this level of increase may play a significant role in the radioenhancement observed in UV41 cells because these excision-repair--deficient cells are much more sensitive to carboplatin as measured by cytotoxicity. CONCLUSION: These results suggest that some of the enhanced cell killing that results when cells are exposed to carboplatin in combination with radiation may be attributed to an increased cellular uptake. One mechanism of radiopotentiation may be an enhanced chemotoxicity resulting from a radiation-induced increase in carboplatin uptake.