Two analogues of camptothecin (CPT), topotecan (TPT) and irinotecan (CPT-11), have significant anti-tumor activity in the clinic, although their abilities depend on the CPT E ring lactone, which forms an inactive hydroxy acid at physiological pH. The reaction is reversible at an acidic pH
e
, which provides a rationale for selectivity because many solid tumors, while creating an acidic extracellular environment, maintain a normal intracellular pH [
120]. An acidic pH
e
inhibits cellular uptake of mitoxantrone and topotecan, so that elevation of pH
e
in tumor tissue enhances those drugs’ efficacy [
120,
121]. Because the buffer action is weaker in tumor tissue than normal tissue, NaHCO
3 has much potential to raise pH
e
relatively specifically in tumor tissue [
122,
123]. Acidic pH
e
also plays a role in the resistance of tumor cells to drugs by increasing the expression of p-glycoprotein, thereby increasing drug efflux [
124,
125]. Recently, an acidic pH
e
-specific drug-releasing system has been developed [
126,
127]. A novel polymeric micelle constituted of 2 block copolymers of poly (L-lactic acid)-b-poly(ethylene glycol) b-poly (L-histidine) - TAT (transactivator of transcription) and poly(L-histidine)-b-poly(ethylene glycol) increases the cytotoxicity of doxorubicin in several multidrug-resistant tumor cell lines [
127]. To measure pH
e
, a magnetic resonance image technique has been developed using acidic pH
e
specific probes [
128,
129]. Thus, clinicians should pay attention to tumor pH
e
in selecting drugs and helping to maximize their chemotherapeutic action. Vasodilating drugs, such as hydralazine and captopril, inhibit tumor growth rate
in vivo by reducing tumor blood flow [
130]. Although the reduction in tumor growth by those drugs also reduces the oxygen supply, it reduces pH
e
. In patients given vasodilating drugs, anti-tumor drugs with weak acidic p
K
a
value, such as 5-fluorouracil (5FU) and cyclophosphamide, may have increased efficacy at an acidic pH
e
. In contrast, the anti-tumor drugs with weak base p
Ka values, such as doxorubicin, mitoxantrone and daunorubicin, may not be fully functioned because acidic pH
e
reduces their cytotoxicity [
121,
131]. In early-stage breast cancer, high CAIX is a predictive marker of doxorubicin resistance [
132].
Because
cis-diamminedichloroplatinum (II) (CDDP) solution has an acidic pH, NaHCO
3 is used to prevent the angialgia in the cancer patients coming from the acidic pH solution injection because it increases pH [
133,
134]. However, CDDP is frequently used for co-injection with other chemotherapeutic drugs, such as 5FU. In some cases, co-injection of NaHCO
3 (depends on the concentration) may reduce the clinical efficacy of 5FU + CDDP regimen.