Zajicek G
Med Hypotheses. 1986 Feb;19(2):103-12. doi: 10.1016/0306-9877(86)90051-4.
Human cancers are either refractory to chemotherapy, or acquire resistance to it. Although acquired resistance to chemotherapy is generally ascribed to the drug itself, it may be linked with the nature of neoplasia, since normal tissues e.g. gastrointestinal mucosa or bone marrow, do not seem to acquire resistance and their perpetuating sensitivity even undermines effective treatment. According to the theory presented herewith, chemotherapy ultimately fails since it is based on wrong premises. Cancer is regarded here as a metabolic deficiency, originating in stem cell destruction. Besides serving as tissue progenitors, stem cells are postulated to secrete a vital substance 'A' necessary for proper tissue function. Carcinogens interfere with 'A' production mainly by destroying stem cells, which the organism is incapable of fully replenishing, so that less 'A' is produced. This irreversible 'A' deficiency may be replenished solely by a substitute, or substance 'B', produced by a specialized organ, the neoplasm. Since carcinogens continue depleting additional stem cells, the deficiency worsens. In order to keep up with increasing demand the neoplasm has to proliferate more and more until it reaches a stage of decompensation when the harm inflicted by it outweighs its benefit. Stem cell depletion is regarded here as the common final pathway of carcinogens. The theory predicts that following a supply of 'A' producing stem cells or inactivated 'B' producing neoplastic stem cells, the tumor will regress. Tumor regression is achievable also by diminishing the demand for the missing metabolites, which may be accomplished by chemotherapy. 'A' and 'B' are consumed mainly by transitional cells. Upon their elimination the demand for 'A' declines and the tumor may wane. This is regarded here as the main role of chemotherapy in cancer, while its tumoricidal potency is indicated solely for repairing tumor induced function loss. It is proposed here that the good response to chemotherapy by Hodgkin's disease and seminoma is linked with their being partially infective. Both start as genuine smouldering infections turning later into neoplasms. While chemotherapy is adequate only during the infective phase, it is met with mounting resistance when applied during the neoplastic phase.
人类癌症要么对化疗难治，要么会产生化疗耐药性。虽然获得性化疗耐药性通常归因于药物本身，但它可能与肿瘤形成的本质有关，因为正常组织，如胃肠道黏膜或骨髓，似乎不会产生耐药性，而且它们持续的敏感性甚至会影响有效治疗。根据本文提出的理论，化疗最终失败是因为它基于错误的前提。这里将癌症视为一种代谢缺陷，起源于干细胞破坏。除了作为组织祖细胞外，干细胞被假定分泌一种对组织正常功能至关重要的物质“A”。致癌物主要通过破坏干细胞来干扰“A”的产生，而机体无法完全补充这些干细胞，从而导致“A”的产生减少。这种不可逆的“A”缺乏只能通过一种替代物或由专门器官即肿瘤产生的物质“B”来补充。由于致癌物继续消耗更多的干细胞，缺乏情况会恶化。为了满足不断增加的需求，肿瘤不得不越来越多地增殖，直到达到失代偿阶段，此时它造成的危害超过了益处。这里将干细胞耗竭视为致癌物的共同最终途径。该理论预测，在供应产生“A”的干细胞或失活的产生“B”的肿瘤干细胞后，肿瘤将会消退。通过减少对缺失代谢物的需求也可以实现肿瘤消退，这可以通过化疗来完成。“A”和“B”主要被过渡细胞消耗。消除这些细胞后，对“A”的需求下降，肿瘤可能会消退。这里将这视为化疗在癌症中的主要作用，而其杀肿瘤效力仅用于修复肿瘤引起的功能丧失。本文提出，霍奇金病和精原细胞瘤对化疗的良好反应与它们部分具有感染性有关。两者起初都是真正的潜伏性感染，后来转变为肿瘤。虽然化疗仅在感染阶段有效，但在肿瘤阶段应用时会遇到越来越大的耐药性。
