Electrochemical red-ox therapy of prostate cancer in nude mice.

Minimally invasive therapies are increasingly in demand for organ-confined prostate tumors. Electrochemical therapy (EChT) is attractive, as it relies on locally-induced reduction-oxidation reactions to kill tumor cells. Its efficacy for prostate cancer was assessed in human PC-3 and LNCaP tumor xenografts growing subcutaneously in nude mice (n = 80) by applying 2 Stainless Steel vs. 4 Platinum-Iridium (Pt-Ir) electrodes to deliver current densities of 10 to 35 mA/cm(2) for 30 or 60 min. The procedure was uneventful in 90% of mice. No difference in tumor vs. body temperature was observed. Changes at electrode-tumor junctions were immediate, with dryness and acidity (pH2-3) at the anode and oedema and alkalinity (pH10-12) at the cathode. This was accompanied by cellular alterations, found more pronounced at the cathode. Such acidic and alkaline conditions were cytotoxic in vitro and dissolved cells at pH>10. In mice, tumor destruction was extensive by 24h with almost undetectable blood prostate specific antigen (LNCaP model) and covered the whole tumor surface by 4 days. EChT was most efficient at 25-30 mA/cm(2) for 60 min, yielding the longest recurrence-free survival and higher cure rates, especially with 4 Pt-Ir electrodes. EChT is a promising option to optimize for organ-confined prostate tumors.

High infectious burden, low cancer incidence, and early malignancy in developing countries: a molecular hypothesis in term of the role of nitric oxide.

Nitric oxide (NO) is a neurotransmitter which plays a powerful role in the immune system: it kills bacteria, and, it also destroys the tumor cells. Specifically, immune system stimuli gamma interferon and lipopolysaccharide transmit signals to a macrophage nucleus causing the production of nitric oxide synthase, the enzyme that converts arginine to NO. The NO thus produced not only destroys bacteria but also attacks the tumor cells by inhibiting the energy-producing Krebs cycle, electron transport activity and DNA synthesis. People in developing countries who survive repeated childhood infections must be inferred to have robust microphage/NO systems and thus, also, a strong immunity against cancer--thence the low incidence of cancers in these countries. However, those unfortunate few in these countries who do develop cancer, despite a robust microphage/NO system, must be presumed to have a markedly virulent tumor development micro-environment (e.g., activation of tumor promotion genes, inactivation of tumor suppression genes, multiple mutations, etc.) that escapes even the particularly alert immune surveillance--thence the earlier (by about a decade) death by cancer in those countries. Thus the NO hypothesis put forward here simultaneously provides a mechanistic causation for (i) low cancer incidence in countries subjected to heavy infectious burdens, and (ii) the earlier occurrence (by about a decade) of major cancers in those countries when the immune surveillance, despite its robustness, fails to destroy the incipient formation of cancer cells.

Inverse trend between estimated worldwide frequency of major cancers and inferred infectious burdens of populations: possible role of adaptive immune system.

Regions of the world subjected to heavy infectious burdens seem to show lower incidence of cancer. The index of infectious burden in this study has been chosen to be poverty, i.e., low GDP, high infantile mortality, poor hygienic conditions, inaccessibility to modern medical infra-structures, etc. When estimates of observed cancer incidence is plotted against the GDP of 24 regions of the world, a trend line is obtained: low GDP (a proxy for high infectious burden) tends to be associated with low incidence of cancer whereas high GDP values herald higher cancer occurrences. Similarly, countries with high infantile mortality rates tend to have a lower incidence of cancer and vice versa. The data are explained in terms of the so-called "hygiene hypothesis": frequent infectious onslaughts, especially in childhood, challenge the immune system and build a strong adaptive immune system and immunological memory which prepare the body to tackle further battles down the line, such as cancer. Within this framework, the role of other factors such as diet, selenium, hardness of water, etc. in the aetiology of cancer is also briefly examined. For rigorous verification of this observation, age-adjusted cancer incidence rates for various countries must be used even though such data are not available for all the countries examined here [Bulletin of World Health Organization 62(2) (1984) 163]; where data are available [Age-adjusted death rates for cancer for selected sites (A classification) in 51 countries in 1974, Segi Institute of Cancer Epidemiology, Nagoya, Japan (Feb. 1979); Global Geocancerology, Churchill Livingstone, New York, 1986], the same trend is also observed for the age-adjusted cancer death rates, which may be used as an index of age-adjusted cancer incidence, subject to qualifications discussed in the text.

Observations on the proposed relationship between infection burden and early malignancy in developing countries (e.g., India).

Sastry and Parikh [Med. Hypotheses 60(4) (2003) 573] have recently sought an explanation for the fact that the occurrence of a particular cancer in populations in a developing country such as India takes place at a younger age (about one decade) than in populations in Western countries. They have hypothesized that a higher infectious burden in India gives rise to repeated cell divisions leading to early senescence of immune cells, and, thence their reduced ability for immune surveillance against cancer, resulting in earlier onset of cancer. The analysis presented here points out to some difficulties with this interpretation, both on empirical and theoretical grounds. The reduced surveillance ability, caused by higher infectious burden, of the immune cells postulated by Sastry and Parikh [loc. cit.] would also mean that populations in India should suffer higher incidence of cancer, as compared to people in Western countries; the empirical data show that, in fact, quite the opposite is true - in the present communication shows that for many common cancers, typical cities in India show the lowest incidence. Theoretically, it is postulated here that repeated heavy infections in India, in fact, challenge the immune system, particularly the adaptive immune system and create an immunological memory: this trains and strengthens the immune system against the future battles. Also it is shown that the shortening of the telomeric cap by repeated cell divisions caused by heavy infectious attacks, as argued by Sastry and Parikh [loc. cit.], is not the cause of earlier onset of cancers among Indians; in fact, when telomeric caps become shortened to a critical point, a danger signal is generated arresting the cell cycle - thus, it provides a fundamental mechanism for ordering the cell to cease proliferation. It is suggested that the root of occurrence of cancers at an earlier age in India perhaps lies in the accumulation of mutations at an earlier age among Indians who do develop cancers; the factors responsible for these accelerated mutations are not clear at the present time and need further investigation.